Is HGFAC p.Thr135Pro (c.403A>C) pathogenic?

HGFAC p.Thr135Pro (c.403A>C) is classified Uncertain significance in HGFAC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). AlphaMissense: ambiguous (0.3954); Absent from gnomAD v4.1.

How common is HGFAC p.Thr135Pro (c.403A>C) in the general population?

HGFAC p.Thr135Pro (c.403A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HGFAC p.Thr135Pro (c.403A>C)?

AlphaMissense predicts ambiguous (score 0.3954) — an in-silico prediction, not a clinical call.

HGFAC p.Thr135Pro

c.403A>C · VCV3525364

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3954 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3954	ambiguous
REVEL	0.233	benign-leaning
SaProt	LLR -12.16	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 7,414 bp · p 0.00031 · regional, not allelic
Overall
CADD	21.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HGFAC
Protein: p.Thr135Pro
Coding: c.403A>C
MANE Select: NM_001528
Type: single nucleotide variant
Location: chr4:3443348 (GRCh38)
Gene constraint: LOEUF 1.64 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 7 PDB
Residue 135: 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.Thr135Ile 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-thr135pro (accessed [today's date]).

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