Is ENGASE p.Leu259Val (c.775C>G) pathogenic?

ENGASE p.Leu259Val (c.775C>G) is classified Uncertain significance in ENGASE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-09). AlphaMissense: likely benign (0.1087); Ultra-rare (popmax 0.025%, amr).

How common is ENGASE p.Leu259Val (c.775C>G) in the general population?

ENGASE p.Leu259Val (c.775C>G) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about ENGASE p.Leu259Val (c.775C>G)?

AlphaMissense predicts likely benign (score 0.1087) — an in-silico prediction, not a clinical call.

ENGASE p.Leu259Val

c.775C>G · VCV3508512

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1087 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1087	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -6.22	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 3.9	GERP 0.79, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.15 · regional, not allelic
Overall
CADD	18.99	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 0.025% Admixed American · 15/59,988 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00105% 17/1,613,396 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	3,999
Remaining individualsnot grpmax-eligible	0.0016%	62,448
European (non-Finnish)	8.47e-05%	1,179,999

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.Leu259Val
Coding: c.775C>G
MANE Select: NM_001042573
Type: single nucleotide variant
Location: chr17:79080976 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41

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-leu259val (accessed [today's date]).

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