Is CFHR3 p.Arg288Ile (c.863G>T) pathogenic?

CFHR3 p.Arg288Ile (c.863G>T) is classified Uncertain significance in CFHR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-10). AlphaMissense: likely benign (0.1254); Ultra-rare (popmax 0.0188%, mid).

How common is CFHR3 p.Arg288Ile (c.863G>T) in the general population?

CFHR3 p.Arg288Ile (c.863G>T) is ultra-rare (popmax 0.0188%, mid) (gnomAD).

What do computational predictors say about CFHR3 p.Arg288Ile (c.863G>T)?

AlphaMissense predicts likely benign (score 0.1254) — an in-silico prediction, not a clinical call.

CFHR3 p.Arg288Ile

c.863G>T · VCV3491549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1254 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1254	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.53	GERP -3.6
Regional constraint	o/e 0.95	unconstrained · MANE · 3,283 bp · p 0.67 · regional, not allelic
Overall
CADD	6.668	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0188% Middle Eastern · 1/5,330 alleles

Filtering AF 0.00322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00249% 38/1,525,368 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0188%	5,330
African / African-American	0.0083%	12,043
Remaining individualsnot grpmax-eligible	0.0051%	19,602
South Asian	0.00497%	20,139
European (non-Finnish)	0.00213%	47,000
Admixed American	0.00173%	57,900

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.Arg288Ile
Coding: c.863G>T
MANE Select: NM_021023
Type: single nucleotide variant
Location: chr1:196793383 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 288: a disulfide bond; the sushi 5 domain

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

Similar variants

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
CFHR3 c.58+8A>G Likely benign ★★ same type
CFHR3 c.796+22T>A 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-arg288ile (accessed [today's date]).

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