Is EPB41 p.Ile757Val (c.2269A>G) pathogenic?

EPB41 p.Ile757Val (c.2269A>G) is classified Uncertain significance in EPB41 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-17). AlphaMissense: likely benign (0.0709); Ultra-rare (popmax 0.0703%, sas); Associated with elliptocytosis 1.

What condition is associated with EPB41 p.Ile757Val (c.2269A>G)?

EPB41 p.Ile757Val (c.2269A>G) is associated with elliptocytosis 1 (ClinVar).

How common is EPB41 p.Ile757Val (c.2269A>G) in the general population?

EPB41 p.Ile757Val (c.2269A>G) is ultra-rare (popmax 0.0703%, sas) (gnomAD).

How is Hereditary elliptocytosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EPB41 p.Ile757Val (c.2269A>G)?

AlphaMissense predicts likely benign (score 0.0709) — an in-silico prediction, not a clinical call.

EPB41 p.Ile757Val

c.2269A>G · rs547322551 · VCV2663957

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0709 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0703%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

elliptocytosis 1

Computational evidence

Protein change
AlphaMissense	0.0709	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 97 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0703% South Asian · 64/91,082 alleles

Filtering AF 0.0565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.00446% 72/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0703%	1,423
Remaining individualsnot grpmax-eligible	0.0048%	20,830
European (non-Finnish)	0.000424%	235,978

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EPB41
Protein: p.Ile757Val
Coding: c.2269A>G
MANE Select: NM_001376013
dbSNP: rs547322551
Type: single nucleotide variant
Location: chr1:29097891 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.72 · 3 PDB
Residue 757: the 'c-terminal (ctd)' region

Full EPB41 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

elliptocytosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary elliptocytosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Worldwide)

Similar variants

EPB41 p.Arg471Ter Pathogenic/Likely pathogenic ★★ same condition
EPB41 p.Arg554Ter Pathogenic/Likely pathogenic ★★ same condition
EPB41 p.Arg715Ter Pathogenic ★★ same condition
EPB41 p.Gln274Ter Pathogenic ★★ same condition
EPB41 p.Tyr331Ter Pathogenic/Likely pathogenic ★★ same condition
EPB41 p.Ala259Val Uncertain significance ★★ ⚠ same condition
EPB41 p.Ala502Val Uncertain significance ★★ ⚠ same condition
EPB41 p.Ala535Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/epb41-p-ile757val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown