Is ENGASE p.Pro473Leu (c.1418C>T) pathogenic?

ENGASE p.Pro473Leu (c.1418C>T) is classified Uncertain significance in ENGASE (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-22). AlphaMissense: likely benign (0.1046); Very rare (popmax 0.0099%, sas).

How common is ENGASE p.Pro473Leu (c.1418C>T) in the general population?

ENGASE p.Pro473Leu (c.1418C>T) is very rare (popmax 0.0099%, sas) (gnomAD).

What do computational predictors say about ENGASE p.Pro473Leu (c.1418C>T)?

AlphaMissense predicts likely benign (score 0.1046) — an in-silico prediction, not a clinical call.

ENGASE p.Pro473Leu

c.1418C>T · rs776041947 · VCV2341723

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1046 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0099%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1046	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -10.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.53, phastCons 0.1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.15 · regional, not allelic
Overall
CADD	21.3	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 0.0099% South Asian · 9/90,904 alleles

Filtering AF 0.00515% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00376%

Overall 0.00385% 62/1,610,308 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0099%	10,100
Remaining individualsnot grpmax-eligible	0.00803%	12,457
East Asian	0.00446%	22,431
European (non-Finnish)	0.00364%	27,435
Admixed American	0.00335%	29,815
African / African-American	0.00134%	74,752

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.Pro473Leu
Coding: c.1418C>T
MANE Select: NM_001042573
dbSNP: rs776041947
Type: single nucleotide variant
Location: chr17:79083927 (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-pro473leu (accessed [today's date]).

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