Is EPB41 p.Phe531= (c.1593C>T) pathogenic?

EPB41 p.Phe531= (c.1593C>T) is classified Likely benign in EPB41 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-12). Ultra-rare (popmax 0.01%, amr); Associated with elliptocytosis 1.

What condition is associated with EPB41 p.Phe531= (c.1593C>T)?

EPB41 p.Phe531= (c.1593C>T) is associated with elliptocytosis 1 (ClinVar).

How common is EPB41 p.Phe531= (c.1593C>T) in the general population?

EPB41 p.Phe531= (c.1593C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

How is Hereditary elliptocytosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

EPB41 p.Phe531=

c.1593C>T · rs779972883 · VCV2498399

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

elliptocytosis 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.87	GERP -3.6, phastCons 0.012
Overall
CADD	12.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,992 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00155% 25/1,613,990 alleles · ultra-rare exomes 23/1,461,856 · genomes 2/152,134 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,999
Remaining individualsnot grpmax-eligible	0.0032%	31,240
European (non-Finnish)	0.00144%	69,414

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.Phe531=
Coding: c.1593C>T
MANE Select: NM_001376013
dbSNP: rs779972883
Type: single nucleotide variant
Location: chr1:29039383 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.72 · 3 PDB
Residue 531: the 'hydrophilic' region; 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-phe531 (accessed [today's date]).

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