Is ENG p.Trp261Gly (c.781T>G) pathogenic?

ENG p.Trp261Gly (c.781T>G) is classified Likely pathogenic in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-14). AlphaMissense: likely pathogenic (0.9187); Absent from gnomAD v4.1.

How common is ENG p.Trp261Gly (c.781T>G) in the general population?

ENG p.Trp261Gly (c.781T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ENG p.Trp261Gly (c.781T>G)?

AlphaMissense predicts likely pathogenic (score 0.9187) — an in-silico prediction, not a clinical call.

ENG p.Trp261Gly

c.781T>G · rs1554810223 · VCV439658

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9187 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9187	likely pathogenic ✓ concordant with ClinVar · top 5% in ENG
REVEL	0.693	pathogenic-leaning
SaProt	LLR -18.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 39 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	26.9	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: ENG
Protein: p.Trp261Gly
Coding: c.781T>G
MANE Select: NM_001114753
dbSNP: rs1554810223
Type: single nucleotide variant
Location: chr9:127825266 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 261: a β-strand; a disulfide bond; the 'required for interaction with gdf2' region; the 'or1, c-terminal part' region

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

Similar variants

ENG p.Trp261Ter Pathogenic ★ same residue
ENG p.Trp261Leu Uncertain significance ★ ⚠ same residue
ENG p.Trp261fs Pathogenic ★★ same residue
ENG p.Arg529His Pathogenic ★★★ ⚠ same type
ENG p.Asn423Ser Likely pathogenic ★★★ ⚠ same type
ENG p.Cys382Tyr Pathogenic ★★★ same type
ENG p.Cys549Gly Likely pathogenic ★★★ same type
ENG p.Gly331Ser Pathogenic ★★★ ⚠ 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/eng-p-trp261gly (accessed [today's date]).

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