Is CFH p.Arg441Thr (c.1322G>C) pathogenic?

CFH p.Arg441Thr (c.1322G>C) is classified Uncertain significance in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-29). AlphaMissense: likely benign (0.0892); Very rare (popmax 0.00267%, afr).

How common is CFH p.Arg441Thr (c.1322G>C) in the general population?

CFH p.Arg441Thr (c.1322G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CFH p.Arg441Thr (c.1322G>C)?

AlphaMissense predicts likely benign (score 0.0892) — an in-silico prediction, not a clinical call.

CFH p.Arg441Thr

c.1322G>C · rs750801523 · VCV2155281

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0892 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0892	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -5.94	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 -20	GERP -3.8
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	0.004	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 0.00267% African / African-American · 2/74,836 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000992% 16/1,613,164 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,418
European (non-Finnish)	0.00119%	84,255

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: CFH
Protein: p.Arg441Thr
Coding: c.1322G>C
MANE Select: NM_000186
dbSNP: rs750801523
Type: single nucleotide variant
Location: chr1:196690225 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 441: a disulfide bond; the sushi 7 domain

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

Similar variants

CFH c.1337-2A>G Likely pathogenic ★★ same type
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same type
CFH c.2236+1G>C Likely pathogenic ★★ same type
CFH c.3493+1G>A Pathogenic/Likely pathogenic ★★ same type
CFH c.350+1G>T Pathogenic/Likely pathogenic ★★ same type
CFH c.619+1G>A Pathogenic/Likely pathogenic ★★ same type
CFH p.Arg1215Leu Likely pathogenic ★★ ⚠ same type
CFH p.Arg1215Ter Pathogenic/Likely pathogenic ★★ 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/cfh-p-arg441thr (accessed [today's date]).

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