Is CFHR1 p.Arg305Pro (c.914G>C) pathogenic?

CFHR1 p.Arg305Pro (c.914G>C) is classified Uncertain significance in CFHR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: ambiguous (0.4955); Very rare (popmax 0.000177%, nfe).

How common is CFHR1 p.Arg305Pro (c.914G>C) in the general population?

CFHR1 p.Arg305Pro (c.914G>C) is very rare (popmax 0.000177%, nfe) (gnomAD).

What do computational predictors say about CFHR1 p.Arg305Pro (c.914G>C)?

AlphaMissense predicts ambiguous (score 0.4955) — an in-silico prediction, not a clinical call.

CFHR1 p.Arg305Pro

c.914G>C · VCV3832501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000177%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4955	ambiguous
REVEL	0.285	benign-leaning
SaProt	LLR -15.08	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 -20	GERP -3.5
Regional constraint	o/e 0.72	unconstrained · MANE · 1,496 bp · p 0.00038 · regional, not allelic
Overall
CADD	0.397	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 0.000177% European (non-Finnish) · 2/1,129,278 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000144% 2/1,390,062 alleles · very rare

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.Arg305Pro
Coding: c.914G>C
MANE Select: NM_002113
Type: single nucleotide variant
Location: chr1:196831920 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.21 · 2 PDB
Residue 305: a disulfide bond; the sushi 5 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-arg305pro (accessed [today's date]).

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