Is ENDOV p.Ala220Val (c.659C>T) pathogenic?

ENDOV p.Ala220Val (c.659C>T) is classified Uncertain significance in ENDOV (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-09). AlphaMissense: likely pathogenic (0.6167); Very rare (popmax 0.00172%, amr).

How common is ENDOV p.Ala220Val (c.659C>T) in the general population?

ENDOV p.Ala220Val (c.659C>T) is very rare (popmax 0.00172%, amr) (gnomAD).

What do computational predictors say about ENDOV p.Ala220Val (c.659C>T)?

AlphaMissense predicts likely pathogenic (score 0.6167) — an in-silico prediction, not a clinical call.

ENDOV p.Ala220Val

c.659C>T · VCV3508481

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6167 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00172%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6167	likely pathogenic
REVEL	0.447	indeterminate
SaProt	LLR -12.42	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 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 21 kb · p 0.00075 · regional, not allelic
Overall
CADD	25.1	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 0.00172% Admixed American · 1/58,084 alleles

Overall 6.94e-05% 1/1,440,248 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: ENDOV
Protein: p.Ala220Val
Coding: c.659C>T
MANE Select: NM_173627
Type: single nucleotide variant
Location: chr17:80425565 (GRCh38)
Gene constraint: LOEUF 1.439 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.90 · 2 PDB
Residue 220: an α-helix

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

Similar variants

ENDOV p.His141Tyr Benign ★★ same type
ENDOV p.Ala167Thr 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
ENDOV p.Ala63Gly Uncertain significance ★ ⚠ same type
ENDOV p.Ala65Ser 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-ala220val (accessed [today's date]).

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