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…

Primary Disease Associations & Inheritance

Deafness, autosomal dominant 76MIM #618787

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · autosomal dominant nonsyndromic hearing loss · AD · ClinGen 2026

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.67

LOEUF

GOF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in PLS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

668 rare PASS variants

Rare truncating (LoF)

1 in 1,100

88 rare PASS variants

Rare synonymous (reference)

1 in 200

230 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PLS1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 890
South Asian	~43k	1 in 87	1 in 1,600
Remaining (unassigned)	~30k	1 in 100	1 in 1,200
European (Finnish)	~27k	1 in 220	≈ 1 in 8,900
Admixed American	~22k	1 in 120	≈ 1 in 5,700
African / African American	~21k	1 in 92	1 in 1,500
East Asian	~20k	1 in 130	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 610	1 in 1,700
Middle Eastern	~2,884	1 in 210	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 5 of 15 coding exons well covered in gnomAD exomes; exons 2, 3, 4, 6, 9 and 5 more marginal. Genomes: all 15.? see exons ↓