Is EPB41L3 p.Met826Val (c.2476A>G) pathogenic?

EPB41L3 p.Met826Val (c.2476A>G) is classified Uncertain significance in EPB41L3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). AlphaMissense: likely benign (0.0737); Very rare (popmax 0.00102%, nfe).

How common is EPB41L3 p.Met826Val (c.2476A>G) in the general population?

EPB41L3 p.Met826Val (c.2476A>G) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about EPB41L3 p.Met826Val (c.2476A>G)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

EPB41L3 p.Met826Val

c.2476A>G · VCV3275762

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -6.53	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 1.7	GERP -1.6, phastCons 0.98
Regional constraint	o/e 0.98	unconstrained · MANE · 25 kb · p 0.52 · regional, not allelic
Overall
CADD	13.19	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 0.00102% European (non-Finnish) · 12/1,174,538 alleles

Filtering AF 0.000545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00043%

Overall 0.000748% 12/1,604,584 alleles · very rare exomes 10/1,452,402 · genomes 2/152,182 · joint denominator

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: EPB41L3
Protein: p.Met826Val
Coding: c.2476A>G
MANE Select: NM_012307
Type: single nucleotide variant
Location: chr18:5397423 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.53 · 54 PDB
Residue 826: the 'spectrin--actin-binding' region

Full EPB41L3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPB41L3 p.Ala698Thr Uncertain significance ★★ same type
EPB41L3 p.Leu556Ser Uncertain significance ★★ ⚠ same type
EPB41L3 p.Thr747Ala Uncertain significance ★★ ⚠ same type
EPB41L3 p.Arg498Gln Likely benign ★★ ⚠ same type
EPB41L3 p.Arg924Cys Benign ★★ same type
EPB41L3 p.Asn680Ser Benign ★★ same type
EPB41L3 p.Glu859Gln Benign/Likely benign ★★ same type
EPB41L3 p.Leu759= Benign ★★ same type

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/epb41l3-p-met826val (accessed [today's date]).

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