Is HGFAC p.Gly331Asp (c.992G>A) pathogenic?

HGFAC p.Gly331Asp (c.992G>A) is classified Uncertain significance in HGFAC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely pathogenic (0.873); Very rare (popmax 0.00112%, sas).

How common is HGFAC p.Gly331Asp (c.992G>A) in the general population?

HGFAC p.Gly331Asp (c.992G>A) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about HGFAC p.Gly331Asp (c.992G>A)?

AlphaMissense predicts likely pathogenic (score 0.873) — an in-silico prediction, not a clinical call.

HGFAC p.Gly331Asp

c.992G>A · rs746976598 · VCV2614131

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.873	likely pathogenic
REVEL	0.431	indeterminate
SaProt	LLR -10.65	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 11	GERP 1.3, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 7,414 bp · p 0.00031 · regional, not allelic
Overall
CADD	26.8	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 0.00112% South Asian · 1/89,266 alleles

Overall 6.91e-05% 1/1,447,640 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: HGFAC
Protein: p.Gly331Asp
Coding: c.992G>A
MANE Select: NM_001528
dbSNP: rs746976598
Type: single nucleotide variant
Location: chr4:3444969 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 7 PDB
Residue 331: a disulfide bond; the kringle domain

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

Similar variants

HGFAC p.Ala121Pro Uncertain significance ★ ⚠ same type
HGFAC p.Ala268Ser Uncertain significance ★ ⚠ same type
HGFAC p.Ala274Thr Uncertain significance ★ ⚠ same type
HGFAC p.Ala327Val Uncertain significance ★ ⚠ same type
HGFAC p.Ala328Val Uncertain significance ★ ⚠ same type
HGFAC p.Ala356Val Uncertain significance ★ ⚠ same type
HGFAC p.Ala424Pro Uncertain significance ★ ⚠ same type
HGFAC p.Ala446Ser 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/hgfac-p-gly331asp (accessed [today's date]).

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