Is ENDOV p.Arg231Trp (c.691C>T) pathogenic?

ENDOV p.Arg231Trp (c.691C>T) is classified Uncertain significance in ENDOV (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-02). AlphaMissense: likely pathogenic (0.7684); Ultra-rare (popmax 0.0107%, afr).

How common is ENDOV p.Arg231Trp (c.691C>T) in the general population?

ENDOV p.Arg231Trp (c.691C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about ENDOV p.Arg231Trp (c.691C>T)?

AlphaMissense predicts likely pathogenic (score 0.7684) — an in-silico prediction, not a clinical call.

ENDOV p.Arg231Trp

c.691C>T · rs376958092 · VCV2402903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7684 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7684	likely pathogenic
REVEL	0.275	benign-leaning
SaProt	LLR -13.68	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.60 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 21 kb · p 0.00075 · 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

Grpmax group 0.0107% African / African-American · 8/74,672 alleles

Filtering AF 0.00529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.00252% 40/1,588,228 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,334
Remaining individualsnot grpmax-eligible	0.00811%	12,323
Admixed American	0.00691%	14,469
East Asian	0.00227%	44,000
European (non-Finnish)	0.00188%	53,303

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: ENDOV
Protein: p.Arg231Trp
Coding: c.691C>T
MANE Select: NM_173627
dbSNP: rs376958092
Type: single nucleotide variant
Location: chr17:80425597 (GRCh38)
Gene constraint: LOEUF 1.439 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.90 · 2 PDB
Residue 231: a β-strand

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

Similar variants

ENDOV p.Arg231Gln Uncertain significance ★ ⚠ same residue
ENDOV p.His141Tyr Benign ★★ same type
ENDOV p.Ala167Thr Uncertain significance ★ ⚠ same type
ENDOV p.Ala220Val Uncertain significance ★ ⚠ same type
ENDOV p.Ala239Pro Uncertain significance ★ ⚠ same type
ENDOV p.Ala264Val Uncertain significance ★ ⚠ same type
ENDOV p.Ala35Gly Uncertain significance ★ ⚠ same type
ENDOV p.Ala41Thr 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/endov-p-arg231trp (accessed [today's date]).

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