Is C1R p.Phe318Cys (c.953T>G) pathogenic?

C1R p.Phe318Cys (c.953T>G) is classified Uncertain significance in C1R (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-22). AlphaMissense: likely pathogenic (0.5798); Very rare (popmax 0.00337%, nfe).

How common is C1R p.Phe318Cys (c.953T>G) in the general population?

C1R p.Phe318Cys (c.953T>G) is very rare (popmax 0.00337%, nfe) (gnomAD).

What do computational predictors say about C1R p.Phe318Cys (c.953T>G)?

AlphaMissense predicts likely pathogenic (score 0.5798) — an in-silico prediction, not a clinical call.

C1R p.Phe318Cys

c.953T>G · rs1159906454 · VCV1012819

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00337%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5798	likely pathogenic
REVEL	0.175	moderately benign-leaning
SaProt	LLR -10.80	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.78, phastCons 1
Regional constraint	o/e 1.39	unconstrained · MANE · 10 kb · p 1.4e-08 · regional, not allelic
Overall
CADD	23.3	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

Grpmax group 0.00337% European (non-Finnish) · 14/415,358 alleles

Filtering AF 0.00195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00163%

Overall 0.00194% 15/774,968 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00337%	29,668
African / African-American	0.00169%	59,194

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: C1R
Protein: p.Phe318Cys
Coding: c.953T>G
MANE Select: NM_001733
dbSNP: rs1159906454
Type: single nucleotide variant
Location: chr12:7088695 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 87.33 · 12 PDB
Residue 318: a disulfide bond; the sushi 1 domain

Full C1R gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1R p.Arg301Pro Pathogenic ★★ ⚠ same type
C1R p.Asp290Gly Pathogenic/Likely pathogenic ★★ same type
C1R p.Cys338Arg Pathogenic ★★ same type
C1R p.Cys371Trp Pathogenic ★★ same type
C1R p.Gly297Asp Pathogenic/Likely pathogenic ★★ same type
C1R p.His642Gln Uncertain significance ★★ ⚠ same type
C1R p.Leu285Met Uncertain significance ★★ ⚠ same type
C1R c.1038+151T>C Benign ★★ 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/c1r-p-phe318cys (accessed [today's date]).

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