Is EPB41 p.Arg238Ter (c.712C>T) pathogenic?

EPB41 p.Arg238Ter (c.712C>T) is classified Likely pathogenic in EPB41 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). Very rare (popmax 0.000424%, nfe); Associated with elliptocytosis 1.

What condition is associated with EPB41 p.Arg238Ter (c.712C>T)?

EPB41 p.Arg238Ter (c.712C>T) is associated with elliptocytosis 1 (ClinVar).

How common is EPB41 p.Arg238Ter (c.712C>T) in the general population?

EPB41 p.Arg238Ter (c.712C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Hereditary elliptocytosis inherited?

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

EPB41 p.Arg238Ter

c.712C>T · rs1160118901 · VCV1324333

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

elliptocytosis 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 21
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.40	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 3.4	GERP 1, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,890 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00041% 6/1,461,732 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,024
European (non-Finnish)grpmax	0.000424%	235,978

Finnish 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.Arg238Ter
Coding: c.712C>T
MANE Select: NM_001376013
dbSNP: rs1160118901
Type: single nucleotide variant
Location: chr1:28997245 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.72 · 3 PDB
Residue 238: the ferm domain; an α-helix

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.Arg238Gln 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-arg238ter (accessed [today's date]).

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