Is CFHR3 p.Pro201Ala (c.601C>G) pathogenic?

CFHR3 p.Pro201Ala (c.601C>G) is classified Uncertain significance in CFHR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: ambiguous (0.5086); Ultra-rare (popmax 0.0183%, nfe).

How common is CFHR3 p.Pro201Ala (c.601C>G) in the general population?

CFHR3 p.Pro201Ala (c.601C>G) is ultra-rare (popmax 0.0183%, nfe) (gnomAD).

What do computational predictors say about CFHR3 p.Pro201Ala (c.601C>G)?

AlphaMissense predicts ambiguous (score 0.5086) — an in-silico prediction, not a clinical call.

CFHR3 p.Pro201Ala

c.601C>G · VCV3491546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5086	ambiguous
REVEL	0.238	benign-leaning
SaProt	LLR -11.58	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 1, phastCons 0.12
Regional constraint	o/e 0.72	unconstrained · MANE · 15 kb · p 1.1e-05 · regional, not allelic
Overall
CADD	21.0	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 0.0183% European (non-Finnish) · 207/1,131,918 alleles

Filtering AF 0.0162% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.0137% 209/1,529,266 alleles · ultra-rare exomes 204/1,392,046 · genomes 5/137,220 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0183%	5,468
Remaining individualsnot grpmax-eligible	0.00338%	29,548

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: CFHR3
Protein: p.Pro201Ala
Coding: c.601C>G
MANE Select: NM_021023
Type: single nucleotide variant
Location: chr1:196788386 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 201: the sushi 3 domain

Full CFHR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR3 c.796+1G>A Uncertain significance ★★ same type
CFHR3 p.Arg320Gln Uncertain significance ★★ ⚠ same type
CFHR3 p.Gly119Ala Uncertain significance ★★ ⚠ same type
CFHR3 p.Ile70Thr Uncertain significance ★★ ⚠ same type
CFHR3 p.Tyr118Ter Uncertain significance ★★ same type
CFHR3 c.431-88C>T Benign ★★ same type
CFHR3 c.58+8A>G Likely benign ★★ same type
CFHR3 c.796+22T>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/cfhr3-p-pro201ala (accessed [today's date]).

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