SPTA1

Chr 1ADAR

spectrin alpha, erythrocytic 1

Also known as: EL2, HPP, HS3, SPH3, SPTA

NCBI Gene: 6708 ENSG00000163554 UniProt: P02549 OMIM: 182860

This gene encodes a member of a family of molecular scaffold proteins that link the plasma membrane to the actin cytoskeleton and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. The encoded protein is primarily composed of 22 spectrin repeats which are involved in dimer formation. It forms a component of the erythrocyte plasma membrane. Mutations in this gene result in a variety of hereditary red blood cell disorders, including elliptocytosis-2, pyropoikilocytosis, and spherocytosis, type 3. [provided by RefSeq, Aug 2017]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.493 OMIM phenotypes

Clinical Summary— SPTA1

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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

214 unique Pathogenic / Likely Pathogenic· 806 VUS of 1582 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.000

Z-score 6.75

OE 0.39 (0.32–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-2.25Z-score

OE missense 1.18 (1.13–1.23)

1456 obs / 1233.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.39 (0.32–0.49)

0≤0.351.4

Missense OE?1.18 (1.13–1.23)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 57 / 144.6Missense obs/exp: 1456 / 1233.7Syn Z: -2.89

This gene — mechanism propensity

0.79top 25%

GOF

0.80top 10%

LOF

0.1598th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction 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

1582 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic66

Likely Pathogenic148

VUS806

Likely Benign199

Benign134

Conflicting223

Pathogenic

148

Likely Pathogenic

806

VUS

199

Likely Benign

134

Benign

223

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	59	3	4	0	66
Likely Pathogenic	135	8	3	2	148
VUS	5	702	71	28	806
Likely Benign	0	32	93	74	199
Benign	0	12	95	27	134
Conflicting	—				223
Total	199	757	266	131	1,576

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap SPTA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →