Is ENGASE p.Val6Ala (c.17T>C) pathogenic?

ENGASE p.Val6Ala (c.17T>C) is classified Uncertain significance in ENGASE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.0738); Very rare (popmax 0.00362%, amr).

How common is ENGASE p.Val6Ala (c.17T>C) in the general population?

ENGASE p.Val6Ala (c.17T>C) is very rare (popmax 0.00362%, amr) (gnomAD).

What do computational predictors say about ENGASE p.Val6Ala (c.17T>C)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

ENGASE p.Val6Ala

c.17T>C · VCV4018020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00362%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -5.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.7	GERP -2.4
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.15 · regional, not allelic
Overall
CADD	8.065	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00362% Admixed American · 1/27,590 alleles

Overall 0.00066% 1/151,426 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: ENGASE
Protein: p.Val6Ala
Coding: c.17T>C
MANE Select: NM_001042573
Type: single nucleotide variant
Location: chr17:79074961 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41
Residue 6: the 'disordered' region

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

Similar variants

ENGASE p.Arg555His Benign ★★ same type
ENGASE c.873-1G>A Uncertain significance ★ same type
ENGASE p.Ala107Val Uncertain significance ★ ⚠ same type
ENGASE p.Ala217Asp Uncertain significance ★ ⚠ same type
ENGASE p.Ala244Val Uncertain significance ★ ⚠ same type
ENGASE p.Ala24Gly Uncertain significance ★ ⚠ same type
ENGASE p.Ala420Val Uncertain significance ★ ⚠ same type
ENGASE p.Ala692Thr 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/engase-p-val6ala (accessed [today's date]).

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