PLS1

Chr 3AD

plastin 1

Also known as: DFNA76

NCBI Gene: 5357 ENSG00000120756 UniProt: Q14651 OMIM: 602734

The encoded protein is an actin-bundling protein required for stereocilia formation in the inner ear, where it mediates liquid packing of actin filaments necessary for proper stereocilia dimensions. Mutations cause autosomal dominant deafness (DFNA76). This gene shows very low constraint against loss-of-function variants (pLI 0.00001), suggesting tolerance to complete gene loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. The protein encoded by this gene is a third distinct plastin isoform, which is specifically expressed at high levels in the small intestine. Alternatively spliced transcript variants varying in the 5' UTR, but encoding the same protein, have been found for this gene. A pseudogene of this gene is found on chromosome 11.[provided by RefSeq, Feb 2010]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.671 OMIM phenotype

Clinical Summary— PLS1

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Gene-Disease Validity (ClinGen)

autosomal dominant nonsyndromic hearing loss · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 97 VUS of 163 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.000

Z-score 3.05

OE 0.43 (0.28–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.48Z-score

OE missense 0.77 (0.69–0.85)

252 obs / 327.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.28–0.67)

0≤0.351.4

Missense OE?0.77 (0.69–0.85)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 14 / 32.8Missense obs/exp: 252 / 327.1Syn Z: 1.16

This gene — mechanism propensity

0.5574th %ile

GOF

0.76top 25%

LOF

0.2581th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

163 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic3

VUS97

Likely Benign9

Benign29

Conflicting2

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	2	0	0	3
VUS	2	90	4	1	97
Likely Benign	0	2	1	6	9
Benign	0	4	23	2	29
Conflicting	—				2
Total	3	98	28	9	140

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

18 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap PLS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →