Is ENGASE p.Val327Met (c.979G>A) pathogenic?

ENGASE p.Val327Met (c.979G>A) is classified Uncertain significance in ENGASE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: ambiguous (0.3414); Very rare (popmax 0.00445%, eas).

How common is ENGASE p.Val327Met (c.979G>A) in the general population?

ENGASE p.Val327Met (c.979G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about ENGASE p.Val327Met (c.979G>A)?

AlphaMissense predicts ambiguous (score 0.3414) — an in-silico prediction, not a clinical call.

ENGASE p.Val327Met

c.979G>A · VCV4249030

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3414 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3414	ambiguous
REVEL	0.16	moderately benign-leaning
SaProt	LLR -5.17	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.15 · regional, not allelic
Overall
CADD	29.5	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 0.00445% East Asian · 2/44,896 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000743% 12/1,614,120 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,448
South Asian	0.00329%	30,365
Finnishnot grpmax-eligible	0.00312%	32,024
African / African-American	0.00267%	37,473
European (non-Finnish)	0.000254%	393,346

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.Val327Met
Coding: c.979G>A
MANE Select: NM_001042573
Type: single nucleotide variant
Location: chr17:79082004 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41
Residue 327: the brct domain

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-val327met (accessed [today's date]).

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