Is EPB42 p.Pro231= (c.693G>A) pathogenic?

EPB42 p.Pro231= (c.693G>A) is classified Likely benign in EPB42 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). Ultra-rare (popmax 0.0363%, sas); Associated with hereditary spherocytosis type 5.

What condition is associated with EPB42 p.Pro231= (c.693G>A)?

EPB42 p.Pro231= (c.693G>A) is associated with hereditary spherocytosis type 5 (ClinVar).

How common is EPB42 p.Pro231= (c.693G>A) in the general population?

EPB42 p.Pro231= (c.693G>A) is ultra-rare (popmax 0.0363%, sas) (gnomAD).

How is Hereditary spherocytosis inherited?

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

EPB42 p.Pro231=

c.693G>A · VCV4685740

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0363%, sas)

Conditions

hereditary spherocytosis type 5

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 -9.7	GERP -4.5
Overall
CADD	0.382	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0363% South Asian · 33/90,980 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0232%

Overall 0.00254% 41/1,613,168 alleles · ultra-rare exomes 39/1,460,960 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0363%	2,757
Remaining individualsnot grpmax-eligible	0.0032%	31,230
African / African-American	0.00267%	37,469
European (non-Finnish)	0.000339%	294,901

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: EPB42
Protein: p.Pro231=
Coding: c.693G>A
MANE Select: NM_001114134
Type: single nucleotide variant
Location: chr15:43209413 (GRCh38)
Gene constraint: LOEUF 0.771 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.35 · 13 PDB

Full EPB42 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spherocytosis type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary spherocytosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-5 / 10 000 (Germany)

Similar variants

EPB42 p.Arg259Ter Pathogenic/Likely pathogenic ★★ same condition
EPB42 p.Arg310Gln Likely pathogenic ★★ same condition
EPB42 c.10+51G>A Uncertain significance ★★ same condition
EPB42 p.Ala353Val Uncertain significance ★★ ⚠ same condition
EPB42 p.Ala51Thr Uncertain significance ★★ ⚠ same condition
EPB42 p.Ala566Thr Uncertain significance ★★ ⚠ same condition
EPB42 p.Arg155Cys Uncertain significance ★★ ⚠ same condition
EPB42 p.Arg287His 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/epb42-p-pro231 (accessed [today's date]).

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