Is HGFAC p.Arg3Cys (c.7C>T) pathogenic?

HGFAC p.Arg3Cys (c.7C>T) is classified Uncertain significance in HGFAC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-22). AlphaMissense: likely benign (0.1023); Very rare (popmax 0.00265%, sas).

How common is HGFAC p.Arg3Cys (c.7C>T) in the general population?

HGFAC p.Arg3Cys (c.7C>T) is very rare (popmax 0.00265%, sas) (gnomAD).

What do computational predictors say about HGFAC p.Arg3Cys (c.7C>T)?

AlphaMissense predicts likely benign (score 0.1023) — an in-silico prediction, not a clinical call.

HGFAC p.Arg3Cys

c.7C>T · VCV4034989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1023 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00265%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1023	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -7.44	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 -3.1	GERP -2.3
Regional constraint	o/e 1.12	unconstrained · MANE · 7,414 bp · p 0.00031 · regional, not allelic
Overall
CADD	5.171	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 0.00265% South Asian · 2/75,534 alleles

Filtering AF 0.000439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000165%

Overall 0.000446% 6/1,343,862 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00265%	37,767
European (non-Finnish)	0.000352%	284,144

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.Arg3Cys
Coding: c.7C>T
MANE Select: NM_001528
Type: single nucleotide variant
Location: chr4:3442008 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 7 PDB

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-arg3cys (accessed [today's date]).

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