Is CFHR1 p.Cys237Ser (c.710G>C) pathogenic?

CFHR1 p.Cys237Ser (c.710G>C) is classified Uncertain significance in CFHR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely pathogenic (0.9885); Ultra-rare (popmax 0.0187%, mid).

How common is CFHR1 p.Cys237Ser (c.710G>C) in the general population?

CFHR1 p.Cys237Ser (c.710G>C) is ultra-rare (popmax 0.0187%, mid) (gnomAD).

What do computational predictors say about CFHR1 p.Cys237Ser (c.710G>C)?

AlphaMissense predicts likely pathogenic (score 0.9885) — an in-silico prediction, not a clinical call.

CFHR1 p.Cys237Ser

c.710G>C · VCV3832497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9885 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9885	likely pathogenic · top 1% in CFHR1
REVEL	0.613	indeterminate
SaProt	LLR -13.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 1,496 bp · p 0.00038 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0187% Middle Eastern · 1/5,342 alleles

Filtering AF 0.00242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00152%

Overall 0.00194% 27/1,389,646 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0187%	5,342
South Asian	0.00623%	16,043
Admixed American	0.00346%	28,939
Remaining individualsnot grpmax-eligible	0.0017%	58,954
European (non-Finnish)	0.00159%	62,708

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: CFHR1
Protein: p.Cys237Ser
Coding: c.710G>C
MANE Select: NM_002113
Type: single nucleotide variant
Location: chr1:196830602 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.21 · 2 PDB
Residue 237: a disulfide bond; a β-strand; the sushi 4 domain

Full CFHR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR1 p.Asp218Asn Uncertain significance ★★ ⚠ same type
CFHR1 p.Gln44Ter Uncertain significance ★★ same type
CFHR1 p.Ile214Asn Uncertain significance ★★ ⚠ same type
CFHR1 p.Ile70Val Uncertain significance ★★ ⚠ same type
CFHR1 p.Pro223Leu Uncertain significance ★★ ⚠ same type
CFHR1 p.Tyr304Cys Uncertain significance ★★ ⚠ same type
CFHR1 c.253+108G>C Benign ★★ same type
CFHR1 c.253+213G>A 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/cfhr1-p-cys237ser (accessed [today's date]).

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