Is EFHD1 p.Phe205Ser (c.614T>C) pathogenic?

EFHD1 p.Phe205Ser (c.614T>C) is classified Uncertain significance in EFHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.7356); Very rare (popmax 0.000339%, nfe).

How common is EFHD1 p.Phe205Ser (c.614T>C) in the general population?

EFHD1 p.Phe205Ser (c.614T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about EFHD1 p.Phe205Ser (c.614T>C)?

AlphaMissense predicts likely pathogenic (score 0.7356) — an in-silico prediction, not a clinical call.

EFHD1 p.Phe205Ser

c.614T>C · VCV4247098

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7356 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7356	likely pathogenic
REVEL	0.347	indeterminate
SaProt	LLR -11.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 48 kb · p 0.33 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,046 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,064 alleles · very rare

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.Phe205Ser
Coding: c.614T>C
MANE Select: NM_025202
Type: single nucleotide variant
Location: chr2:232681613 (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-phe205ser (accessed [today's date]).

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