Is CFHR5 p.Pro566Ser (c.1696C>T) pathogenic?

CFHR5 p.Pro566Ser (c.1696C>T) is classified Uncertain significance in CFHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely pathogenic (0.6881); Very rare (popmax 0.000411%).

How common is CFHR5 p.Pro566Ser (c.1696C>T) in the general population?

CFHR5 p.Pro566Ser (c.1696C>T) is very rare (popmax 0.000411%) (gnomAD).

What do computational predictors say about CFHR5 p.Pro566Ser (c.1696C>T)?

AlphaMissense predicts likely pathogenic (score 0.6881) — an in-silico prediction, not a clinical call.

CFHR5 p.Pro566Ser

c.1696C>T · rs748430882 · VCV2682714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000411%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6881	likely pathogenic
REVEL	0.591	indeterminate
SaProt	LLR -13.30	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 1.3	GERP 0.12, phastCons 0.056
Regional constraint	o/e 1.15	unconstrained · MANE · 31 kb · p 0.00015 · regional, not allelic
Overall
CADD	16.71	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 0.000411%

Overall 0.000411% 6/1,459,976 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: CFHR5
Protein: p.Pro566Ser
Coding: c.1696C>T
MANE Select: NM_030787
dbSNP: rs748430882
Type: single nucleotide variant
Location: chr1:197008669 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 566: the sushi 9 domain; a disulfide bond

Full CFHR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR5 p.Pro566Leu Uncertain significance ★★ ⚠ same residue
CFHR5 c.430+5G>T Uncertain significance ★★ same type
CFHR5 c.607+4A>G Uncertain significance ★★ same type
CFHR5 c.608-3T>A Uncertain significance ★★ same type
CFHR5 p.Arg132Gln Uncertain significance ★★ ⚠ same type
CFHR5 p.Arg132Trp Uncertain significance ★★ ⚠ same type
CFHR5 p.Arg354Gly Uncertain significance ★★ ⚠ same type
CFHR5 p.Arg356Cys 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/cfhr5-p-pro566ser (accessed [today's date]).

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