Is CFC1 p.Arg192His (c.575G>A) pathogenic?

CFC1 p.Arg192His (c.575G>A) is classified Uncertain significance in CFC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: likely benign (0.1137); Very rare (popmax 0.0043%, nfe).

How common is CFC1 p.Arg192His (c.575G>A) in the general population?

CFC1 p.Arg192His (c.575G>A) is very rare (popmax 0.0043%, nfe) (gnomAD).

What do computational predictors say about CFC1 p.Arg192His (c.575G>A)?

AlphaMissense predicts likely benign (score 0.1137) — an in-silico prediction, not a clinical call.

CFC1 p.Arg192His

c.575G>A · VCV3900913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1137 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0043%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1137	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -8.98	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 -1.8
Regional constraint	o/e 0.12	constrained · MANE · 6,407 bp · p 3.7e-22 · regional, not allelic
Overall
CADD	16.92	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 0.0043% European (non-Finnish) · 13/302,414 alleles

Filtering AF 0.0025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00194%

Overall 0.00332% 17/512,338 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0043%	23,263
Admixed American	0.00412%	24,272
Remaining individualsnot grpmax-eligible	0.00376%	26,618
Finnishnot grpmax-eligible	0.00317%	31,576
South Asian	0.00219%	45,570

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: CFC1
Protein: p.Arg192His
Coding: c.575G>A
MANE Select: NM_032545
Type: single nucleotide variant
Location: chr2:130592974 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI 0.86 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.18

Full CFC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFC1 p.Gly33Ser Uncertain significance ★★ ⚠ same type
CFC1 p.Ala145Thr Benign ★★ same type
CFC1 p.Arg47Gln Benign ★★ same type
CFC1 p.Asn21= Benign/Likely benign ★★ same type
CFC1 p.Asn21His Benign ★★ same type
CFC1 p.Gly59Arg Likely benign ★★ same type
CFC1 p.Leu202= Benign/Likely benign ★★ same type
CFC1 p.Ala195Val 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/cfc1-p-arg192his (accessed [today's date]).

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