Is CFHR4 p.Arg40Cys (c.118C>T) pathogenic?

CFHR4 p.Arg40Cys (c.118C>T) is classified Conflicting classifications of pathogenicity in CFHR4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-25). AlphaMissense: likely pathogenic (0.6404); Rare (popmax 0.449%, eas); Associated with kidney disorder.

What condition is associated with CFHR4 p.Arg40Cys (c.118C>T)?

CFHR4 p.Arg40Cys (c.118C>T) is associated with kidney disorder (ClinVar).

How common is CFHR4 p.Arg40Cys (c.118C>T) in the general population?

CFHR4 p.Arg40Cys (c.118C>T) is rare (popmax 0.449%, eas) (gnomAD).

What do computational predictors say about CFHR4 p.Arg40Cys (c.118C>T)?

AlphaMissense predicts likely pathogenic (score 0.6404) — an in-silico prediction, not a clinical call.

CFHR4 p.Arg40Cys

c.118C>T · rs200339924 · VCV1712440

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6404 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.449%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.6404	likely pathogenic
REVEL	0.103	moderately benign-leaning
SaProt	LLR -11.36	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP -15	GERP -3.3
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	10.39	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 0.449% East Asian · 201/44,804 alleles

Filtering AF 0.398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.378%

Overall 0.019% 306/1,611,718 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.449%	223
Remaining individualsnot grpmax-eligible	0.016%	6,241
South Asian	0.00769%	13,000
European (non-Finnish)	0.00738%	13,550
African / African-American	0.00134%	74,432

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: CFHR4
Protein: p.Arg40Cys
Coding: c.118C>T
MANE Select: NM_001201550
dbSNP: rs200339924
Type: single nucleotide variant
Location: chr1:196902477 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 40: the sushi 1 domain

Full CFHR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR4 p.Arg40His Uncertain significance ★★ ⚠ same residue
CFHR4 p.Tyr35His Likely benign ★★ same condition
CFHR4 p.Ala159Val Uncertain significance ★★ ⚠ same type
CFHR4 p.Ile318Thr Uncertain significance ★★ ⚠ same type
CFHR4 p.Ser199Tyr Uncertain significance ★★ ⚠ same type
CFHR4 p.Ser507Leu Uncertain significance ★★ ⚠ same type
CFHR4 p.Trp68Ter Uncertain significance ★★ same type
CFHR4 p.Tyr238Ser 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/cfhr4-p-arg40cys (accessed [today's date]).

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