Is CFHR3 p.Arg39Cys (c.115C>T) pathogenic?

CFHR3 p.Arg39Cys (c.115C>T) is classified Uncertain significance in CFHR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-23). AlphaMissense: ambiguous (0.5161); Ultra-rare (popmax 0.0824%, amr).

How common is CFHR3 p.Arg39Cys (c.115C>T) in the general population?

CFHR3 p.Arg39Cys (c.115C>T) is ultra-rare (popmax 0.0824%, amr) (gnomAD).

What do computational predictors say about CFHR3 p.Arg39Cys (c.115C>T)?

AlphaMissense predicts ambiguous (score 0.5161) — an in-silico prediction, not a clinical call.

CFHR3 p.Arg39Cys

c.115C>T · rs143890724 · VCV2682693

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5161 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0824%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5161	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -8.18	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.2	GERP -3.7
Regional constraint	o/e 0.72	unconstrained · MANE · 15 kb · p 1.1e-05 · regional, not allelic
Overall
CADD	6.694	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 0.0824% Admixed American · 48/58,224 alleles

Filtering AF 0.0638% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0572%

Overall 0.0121% 185/1,529,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0824%	1,213
East Asian	0.0135%	7,434
European (non-Finnish)	0.0107%	9,337
African / African-American	0.00661%	15,119
South Asian	0.00621%	16,116
Ashkenazi Jewishnot grpmax-eligible	0.00363%	27,550

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.Arg39Cys
Coding: c.115C>T
MANE Select: NM_021023
dbSNP: rs143890724
Type: single nucleotide variant
Location: chr1:196779218 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 39: a disulfide bond; the sushi 1 domain

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

Similar variants

CFHR3 p.Arg39His Conflicting classifications of pathogenicity ★ ⚠ same residue
CFHR3 p.Arg39Leu Uncertain significance ★ ⚠ same residue
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

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-arg39cys (accessed [today's date]).

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