Is CFHR5 p.Cys431Arg (c.1291T>C) pathogenic?

CFHR5 p.Cys431Arg (c.1291T>C) is classified Uncertain significance in CFHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). AlphaMissense: likely pathogenic (0.9758); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with CFHR5 p.Cys431Arg (c.1291T>C)?

CFHR5 p.Cys431Arg (c.1291T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CFHR5 p.Cys431Arg (c.1291T>C) in the general population?

CFHR5 p.Cys431Arg (c.1291T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CFHR5 p.Cys431Arg (c.1291T>C)?

AlphaMissense predicts likely pathogenic (score 0.9758) — an in-silico prediction, not a clinical call.

CFHR5 p.Cys431Arg

c.1291T>C · rs756308122 · VCV3143824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9758	likely pathogenic · top 1% in CFHR5
REVEL	0.637	indeterminate
SaProt	LLR -13.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.35	donor gain · deltas
Constraint at this position
Conservation	phyloP 3.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 31 kb · p 0.00015 · regional, not allelic
Overall
CADD	24.5	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 0.00267% African / African-American · 2/75,004 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000616% 9/1,461,332 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,502
South Asian	0.0022%	45,528
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.000339%	294,929

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.Cys431Arg
Coding: c.1291T>C
MANE Select: NM_030787
dbSNP: rs756308122
Type: single nucleotide variant
Location: chr1:197002625 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 431: a disulfide bond; the sushi 7 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR5 p.Arg132Gln Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg132Trp Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg356Cys Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg364Ser Uncertain significance ★★ ⚠ same condition
CFHR5 p.Asn126His Uncertain significance ★★ ⚠ same condition
CFHR5 p.Asn230Asp Uncertain significance ★★ ⚠ same condition
CFHR5 p.Asp24Ala Uncertain significance ★★ ⚠ same condition
CFHR5 p.Asp535Gly Uncertain significance ★★ ⚠ same condition

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-cys431arg (accessed [today's date]).

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