Is EFHC2 p.Ser500Phe (c.1499C>T) pathogenic?

EFHC2 p.Ser500Phe (c.1499C>T) is classified Uncertain significance in EFHC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). AlphaMissense: likely pathogenic (0.6786); Absent from gnomAD v4.1.

How common is EFHC2 p.Ser500Phe (c.1499C>T) in the general population?

EFHC2 p.Ser500Phe (c.1499C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EFHC2 p.Ser500Phe (c.1499C>T)?

AlphaMissense predicts likely pathogenic (score 0.6786) — an in-silico prediction, not a clinical call.

EFHC2 p.Ser500Phe

c.1499C>T · VCV4016549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6786 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6786	likely pathogenic
REVEL	0.444	indeterminate
SaProt	LLR -8.57	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 3.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 195 kb · p 0.037 · regional, not allelic
Overall
CADD	22.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: EFHC2
Protein: p.Ser500Phe
Coding: c.1499C>T
MANE Select: NM_025184
Type: single nucleotide variant
Location: chrX:44232602 (GRCh38)
Structure: AlphaFold pLDDT 79.83 · 4 PDB
Residue 500: the dm10 3 domain

Full EFHC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EFHC2 p.Glu506Lys Likely benign ★★ ⚠ same type
EFHC2 p.Glu507Gln Benign ★★ ⚠ same type
EFHC2 p.Ala549Gly Uncertain significance ★ ⚠ same type
EFHC2 p.Ala697Ser Uncertain significance ★ ⚠ same type
EFHC2 p.Arg133His Uncertain significance ★ ⚠ same type
EFHC2 p.Arg135Gln Conflicting classifications of pathogenicity ★ ⚠ same type
EFHC2 p.Arg135Trp Uncertain significance ★ ⚠ same type
EFHC2 p.Arg163Gln 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/efhc2-p-ser500phe (accessed [today's date]).

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