Is EFHD1 p.Pro80Ser (c.238C>T) pathogenic?

EFHD1 p.Pro80Ser (c.238C>T) is classified Uncertain significance in EFHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-30). AlphaMissense: ambiguous (0.4981); Very rare (popmax 0.00382%, nfe).

How common is EFHD1 p.Pro80Ser (c.238C>T) in the general population?

EFHD1 p.Pro80Ser (c.238C>T) is very rare (popmax 0.00382%, nfe) (gnomAD).

What do computational predictors say about EFHD1 p.Pro80Ser (c.238C>T)?

AlphaMissense predicts ambiguous (score 0.4981) — an in-silico prediction, not a clinical call.

EFHD1 p.Pro80Ser

c.238C>T · rs781383116 · VCV2354819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00382%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4981	ambiguous
REVEL	0.584	indeterminate
SaProt	LLR -10.63	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	26.1	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 0.00382% European (non-Finnish) · 45/1,179,244 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00294% 47/1,597,332 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00382%	26,205
African / African-American	0.00267%	37,410

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: EFHD1
Protein: p.Pro80Ser
Coding: c.238C>T
MANE Select: NM_025202
dbSNP: rs781383116
Type: single nucleotide variant
Location: chr2:232633942 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.10

Full EFHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFHD1 p.Ala124Thr Uncertain significance ★ ⚠ same type
EFHD1 p.Ala159Val Uncertain significance ★ ⚠ same type
EFHD1 p.Ala19Asp Uncertain significance ★ ⚠ same type
EFHD1 p.Ala49Pro Uncertain significance ★ ⚠ same type
EFHD1 p.Arg13Trp Uncertain significance ★ ⚠ same type
EFHD1 p.Arg149Gln Uncertain significance ★ ⚠ same type
EFHD1 p.Arg218Trp Uncertain significance ★ ⚠ same type
EFHD1 p.Arg224Gly Uncertain significance ★ ⚠ same type

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/efhd1-p-pro80ser (accessed [today's date]).

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