Is HGFAC p.Arg650Trp (c.1948C>T) pathogenic?

HGFAC p.Arg650Trp (c.1948C>T) is classified Uncertain significance in HGFAC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.1438); Ultra-rare (popmax 0.0169%, mid).

How common is HGFAC p.Arg650Trp (c.1948C>T) in the general population?

HGFAC p.Arg650Trp (c.1948C>T) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

What do computational predictors say about HGFAC p.Arg650Trp (c.1948C>T)?

AlphaMissense predicts likely benign (score 0.1438) — an in-silico prediction, not a clinical call.

HGFAC p.Arg650Trp

c.1948C>T · VCV4034975

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1438 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1438	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -9.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.64	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.27	GERP -0.89, phastCons 0.98
Regional constraint	o/e 1.12	unconstrained · MANE · 7,414 bp · p 0.00031 · regional, not allelic
Overall
CADD	24.0	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 0.0169% Middle Eastern · 1/5,908 alleles

Filtering AF 0.00113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000922%

Overall 0.00185% 29/1,563,570 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,908
Remaining individualsnot grpmax-eligible	0.00333%	30,045
African / African-American	0.00273%	36,642
East Asian	0.00235%	42,464
South Asian	0.00235%	42,509
European (non-Finnish)	0.00174%	57,547
Finnishnot grpmax-eligible	0.00162%	61,720

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.Arg650Trp
Coding: c.1948C>T
MANE Select: NM_001528
Type: single nucleotide variant
Location: chr4:3449399 (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-arg650trp (accessed [today's date]).

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