Is CFHR3 p.Arg142Cys (c.424C>T) pathogenic?

CFHR3 p.Arg142Cys (c.424C>T) is classified Benign in CFHR3 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-10-18). AlphaMissense: ambiguous (0.4954); Common (popmax 7.62%, afr) — too common for a highly-penetrant pathogenic allele; Associated with age related macular degeneration 1.

What condition is associated with CFHR3 p.Arg142Cys (c.424C>T)?

CFHR3 p.Arg142Cys (c.424C>T) is associated with age related macular degeneration 1, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

What do computational predictors say about CFHR3 p.Arg142Cys (c.424C>T)?

AlphaMissense predicts ambiguous (score 0.4954) — an in-silico prediction, not a clinical call.

CFHR3 p.Arg142Cys

Q: How common is CFHR3 p.Arg142Cys (c.424C>T) in the general population?

CFHR3 p.Arg142Cys (c.424C>T) is common (popmax 7.62%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.424C>T · rs61737525 · VCV775633

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4954 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.62%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

age related macular degeneration 1

Computational evidence

Protein change
AlphaMissense	0.4954	ambiguous
REVEL	0.135	moderately benign-leaning
SaProt	LLR -10.31	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 -13	GERP -3.1
Regional constraint	o/e 0.72	unconstrained · MANE · 15 kb · p 1.1e-05 · regional, not allelic
Overall
CADD	18.73	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 7.62% African / African-American · 4,609/60,452 alleles

Filtering AF 7.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.37%

Overall 0.411% 6,298/1,532,622 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.62%	13
East Asian	1.75%	57
Middle Eastern	0.746%	134
Remaining individualsnot grpmax-eligible	0.584%	171
Admixed American	0.378%	265
South Asian	0.13%	768
European (non-Finnish)	0.0172%	5,810

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.Arg142Cys
Coding: c.424C>T
MANE Select: NM_021023
dbSNP: rs61737525
Type: single nucleotide variant
Location: chr1:196779967 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 142: the sushi 2 domain

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

Disease context

Also linked: hemolytic uremic syndrome, atypical, susceptibility to, 1

Similar variants

CFHR3 p.Arg142His Uncertain significance ★ ⚠ same residue
CFHR3 p.Cys268Phe Likely benign ★★ same condition
CFHR3 p.Gln240His Benign ★★ ⚠ same condition
CFHR3 p.Ile269Val Likely benign ★★ same condition
CFHR3 p.Ile312Phe Benign/Likely benign ★★ same condition
CFHR3 p.Phe34Cys Benign/Likely benign ★★ ⚠ same condition
CFHR3 p.Gly178= Uncertain significance ★ same condition
CFHR3 p.Ile280fs 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/cfhr3-p-arg142cys (accessed [today's date]).

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