Is HGFAC p.Ser457Arg (c.1371C>A) pathogenic?

HGFAC p.Ser457Arg (c.1371C>A) is classified Uncertain significance in HGFAC (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-25). AlphaMissense: likely benign (0.179); Ultra-rare (popmax 0.0165%, mid).

How common is HGFAC p.Ser457Arg (c.1371C>A) in the general population?

HGFAC p.Ser457Arg (c.1371C>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about HGFAC p.Ser457Arg (c.1371C>A)?

AlphaMissense predicts likely benign (score 0.179) — an in-silico prediction, not a clinical call.

HGFAC p.Ser457Arg

c.1371C>A · VCV4840455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.179 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.179	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4	GERP -2.3
Regional constraint	o/e 1.12	unconstrained · MANE · 7,414 bp · p 0.00031 · regional, not allelic
Overall
CADD	0.031	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,460,278 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
European (non-Finnish)	0.000254%	393,289

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.Ser457Arg
Coding: c.1371C>A
MANE Select: NM_001528
Type: single nucleotide variant
Location: chr4:3447507 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 7 PDB
Residue 457: a disulfide bond; an α-helix; the peptidase s1 domain

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

Similar variants

HGFAC p.Ser457Asn Uncertain significance ★ ⚠ same residue
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

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-ser457arg (accessed [today's date]).

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