Is EPB41 p.Lys88Arg (c.263A>G) pathogenic?

EPB41 p.Lys88Arg (c.263A>G) is classified Conflicting classifications of pathogenicity in EPB41 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.0809); Rare (popmax 0.421%, afr); Associated with elliptocytosis 1.

What condition is associated with EPB41 p.Lys88Arg (c.263A>G)?

EPB41 p.Lys88Arg (c.263A>G) is associated with elliptocytosis 1 (ClinVar).

How common is EPB41 p.Lys88Arg (c.263A>G) in the general population?

EPB41 p.Lys88Arg (c.263A>G) is rare (popmax 0.421%, afr) (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.Lys88Arg (c.263A>G)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

EPB41 p.Lys88Arg

c.263A>G · rs141680585 · VCV2428563

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.421%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

elliptocytosis 1

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -6.83	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 6.2	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 31 kb · p 0.042 · regional, not allelic
Overall
CADD	20.2	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 0.421% African / African-American · 316/75,054 alleles

Filtering AF 0.383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.368%

Overall 0.0213% 344/1,614,204 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.421%	238
Remaining individualsnot grpmax-eligible	0.0288%	3,473
Middle Eastern	0.0165%	6,062
Admixed American	0.01%	10,003
European (non-Finnish)	0.000254%	393,348

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.Lys88Arg
Coding: c.263A>G
MANE Select: NM_001376013
dbSNP: rs141680585
Type: single nucleotide variant
Location: chr1:28987700 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.72 · 3 PDB
Residue 88: the 'disordered' 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-lys88arg (accessed [today's date]).

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