Is HGFAC p.Pro111Ala (c.331C>G) pathogenic?

HGFAC p.Pro111Ala (c.331C>G) is classified Uncertain significance in HGFAC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-23). AlphaMissense: likely pathogenic (0.8756); Very rare (popmax 0.00187%, nfe).

How common is HGFAC p.Pro111Ala (c.331C>G) in the general population?

HGFAC p.Pro111Ala (c.331C>G) is very rare (popmax 0.00187%, nfe) (gnomAD).

What do computational predictors say about HGFAC p.Pro111Ala (c.331C>G)?

AlphaMissense predicts likely pathogenic (score 0.8756) — an in-silico prediction, not a clinical call.

HGFAC p.Pro111Ala

c.331C>G · VCV3857710

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8756	likely pathogenic
REVEL	0.522	indeterminate
SaProt	LLR -11.54	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.30	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.4	GERP 0.21, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 7,414 bp · p 0.00031 · regional, not allelic
Overall
CADD	27.1	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 0.00187% European (non-Finnish) · 22/1,178,636 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00156% 25/1,599,352 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00187%	53,574
Remaining individualsnot grpmax-eligible	0.00161%	62,190
African / African-American	0.00134%	74,854
South Asian	0.0011%	90,614

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.Pro111Ala
Coding: c.331C>G
MANE Select: NM_001528
Type: single nucleotide variant
Location: chr4:3443082 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 7 PDB
Residue 111: a disulfide bond; the fibronectin type-ii 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-pro111ala (accessed [today's date]).

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