Is ENTREP1 p.Cys254Phe (c.761G>T) pathogenic?

ENTREP1 p.Cys254Phe (c.761G>T) is classified Uncertain significance in ENTREP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely pathogenic (0.9656); Very rare (popmax 0.00333%, amr).

How common is ENTREP1 p.Cys254Phe (c.761G>T) in the general population?

ENTREP1 p.Cys254Phe (c.761G>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ENTREP1 p.Cys254Phe (c.761G>T)?

AlphaMissense predicts likely pathogenic (score 0.9656) — an in-silico prediction, not a clinical call.

ENTREP1 p.Cys254Phe

c.761G>T · VCV3508767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9656	likely pathogenic · top 7% in ENTREP1
REVEL	0.584	indeterminate
SaProt	LLR -8.14	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 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 58 kb · p 0.22 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C101F vs ClinVar C254F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,990 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000929% 15/1,613,946 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,995
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00102%	98,333

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: ENTREP1
Protein: p.Cys254Phe
Coding: c.761G>T
MANE Select: NM_001347995
Type: single nucleotide variant
Location: chr9:69377419 (GRCh38)
Structure: AlphaFold pLDDT 60.47
Residue 254: the 'mediates interaction with epn1' region; the 'disordered' region

Full ENTREP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ENTREP1 p.Ala374Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala418Asp Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala440Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala440Thr Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala448Ser Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala492Val Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala574Pro Uncertain significance ★ ⚠ same type
ENTREP1 p.Ala588Val Conflicting classifications of pathogenicity ★ ⚠ 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/entrep1-p-cys254phe (accessed [today's date]).

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