Is EPB41 p.Val214Ile (c.640G>A) pathogenic?

EPB41 p.Val214Ile (c.640G>A) is classified Benign/Likely benign in EPB41 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0831); Common (popmax 6.39%, mid) — too common for a highly-penetrant pathogenic allele; Associated with elliptocytosis 1.

What condition is associated with EPB41 p.Val214Ile (c.640G>A)?

EPB41 p.Val214Ile (c.640G>A) is associated with elliptocytosis 1 (ClinVar).

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.Val214Ile (c.640G>A)?

AlphaMissense predicts likely benign (score 0.0831) — an in-silico prediction, not a clinical call.

EPB41 p.Val214Ile

Q: How common is EPB41 p.Val214Ile (c.640G>A) in the general population?

EPB41 p.Val214Ile (c.640G>A) is common (popmax 6.39%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.640G>A · rs111642750 · VCV811532

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0831 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.39%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

elliptocytosis 1

Computational evidence

Protein change
AlphaMissense	0.0831	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -9.35	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 3.1	GERP 0.87, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 31 kb · p 0.042 · regional, not allelic
Overall
CADD	21.4	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 6.39% Middle Eastern · 387/6,054 alleles

Filtering AF 5.87% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.66%

Overall 4.27% 68,907/1,613,946 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	9.1%	11
Middle Easterngrpmax	6.39%	16
Ashkenazi Jewishnot grpmax-eligible	6.14%	16
European (non-Finnish)	4.96%	20
Remaining individualsnot grpmax-eligible	4.12%	24
Admixed American	3.58%	28
Finnishnot grpmax-eligible	2.36%	42
South Asian	1.34%	75
African / African-American	0.774%	129
East Asian	0.00446%	22,430

Amish 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.Val214Ile
Coding: c.640G>A
MANE Select: NM_001376013
dbSNP: rs111642750
Type: single nucleotide variant
Location: chr1:28993501 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.72 · 3 PDB
Residue 214: the ferm domain; a UniProt-annotated variant site (in); a β-strand

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.Val214Leu Uncertain significance ★★ ⚠ same residue
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

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-val214ile (accessed [today's date]).

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