Is EPB41 p.Arg557Trp (c.1669C>T) pathogenic?

EPB41 p.Arg557Trp (c.1669C>T) is classified Uncertain significance in EPB41 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). AlphaMissense: likely benign (0.2684); Very rare (popmax 0.00333%, amr).

How common is EPB41 p.Arg557Trp (c.1669C>T) in the general population?

EPB41 p.Arg557Trp (c.1669C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about EPB41 p.Arg557Trp (c.1669C>T)?

AlphaMissense predicts likely benign (score 0.2684) — an in-silico prediction, not a clinical call.

EPB41 p.Arg557Trp

c.1669C>T · VCV3711476

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2684 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2684	likely benign
REVEL	0.534	indeterminate
SaProt	LLR -13.59	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 97 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,022 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00041% 6/1,461,860 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,011
South Asian	0.0011%	91,076
European (non-Finnish)	0.000254%	393,343

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.Arg557Trp
Coding: c.1669C>T
MANE Select: NM_001376013
Type: single nucleotide variant
Location: chr1:29053136 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.72 · 3 PDB
Residue 557: the 'hydrophilic' region; the 'disordered' region

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

Similar variants

EPB41 p.Arg557Gln Uncertain significance ★ ⚠ same residue
EPB41 p.Arg471Ter Pathogenic/Likely pathogenic ★★ same type
EPB41 p.Arg508Ter Pathogenic/Likely pathogenic ★★ same type
EPB41 p.Arg554Ter Pathogenic/Likely pathogenic ★★ same type
EPB41 p.Arg715Ter Pathogenic ★★ same type
EPB41 p.Gln274Ter Pathogenic ★★ same type
EPB41 p.Met210Val Pathogenic/Likely pathogenic ★★ ⚠ same type
EPB41 p.Tyr331Ter Pathogenic/Likely pathogenic ★★ 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/epb41-p-arg557trp (accessed [today's date]).

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