Is EPB41 p.Pro291Ser (c.871C>T) pathogenic?

EPB41 p.Pro291Ser (c.871C>T) is classified Benign/Likely benign in EPB41 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-01). AlphaMissense: likely pathogenic (0.7862); Low-frequency (popmax 1.99%, mid); Associated with elliptocytosis 1.

What condition is associated with EPB41 p.Pro291Ser (c.871C>T)?

EPB41 p.Pro291Ser (c.871C>T) is associated with elliptocytosis 1 (ClinVar).

How common is EPB41 p.Pro291Ser (c.871C>T) in the general population?

EPB41 p.Pro291Ser (c.871C>T) is low-frequency (popmax 1.99%, mid) (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.Pro291Ser (c.871C>T)?

AlphaMissense predicts likely pathogenic (score 0.7862) — an in-silico prediction, not a clinical call.

EPB41 p.Pro291Ser

c.871C>T · rs142874233 · VCV618089

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7862 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.99%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

elliptocytosis 1

Computational evidence

Protein change
AlphaMissense	0.7862	likely pathogenic
REVEL	0.427	indeterminate
SaProt	LLR -12.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 31 kb · p 0.042 · regional, not allelic
Overall
CADD	25.7	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 1.99% Middle Eastern · 120/6,022 alleles

Filtering AF 1.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.59%

Overall 0.569% 9,158/1,608,302 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	5.57%	18
Middle Easterngrpmax	1.99%	50
Remaining individualsnot grpmax-eligible	0.904%	111
South Asian	0.609%	164
European (non-Finnish)	0.507%	197
Admixed American	0.238%	419
African / African-American	0.132%	757
Finnishnot grpmax-eligible	0.119%	842
East Asian	0.00446%	22,401

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro291Ser
Coding: c.871C>T
MANE Select: NM_001376013
dbSNP: rs142874233
Type: single nucleotide variant
Location: chr1:29015733 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.72 · 3 PDB
Residue 291: the ferm domain

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-pro291ser (accessed [today's date]).

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