Is CFHR3 p.Pro241Ser (c.721C>T) pathogenic?

CFHR3 p.Pro241Ser (c.721C>T) is classified Benign/Likely benign in CFHR3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0841); Common (popmax 29%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CFHR3 p.Pro241Ser (c.721C>T)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

CFHR3 p.Pro241Ser

Q: How common is CFHR3 p.Pro241Ser (c.721C>T) in the general population?

CFHR3 p.Pro241Ser (c.721C>T) is common (popmax 29%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.721C>T · rs138675433 · VCV778240

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 29%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -5.69	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 -3.6
Regional constraint	o/e 0.30	constrained · MANE · 169 bp · p 1.3e-09 · regional, not allelic
Overall
CADD	0.38	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 29% East Asian · 8,194/28,246 alleles

Filtering AF 28.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.3%

Overall 3.38% 43,590/1,290,644 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	29%	3
Amishnot grpmax-eligible	11.3%	9
African / African-American	10.6%	9
Admixed American	7.74%	13
Remaining individualsnot grpmax-eligible	4.45%	22
Ashkenazi Jewishnot grpmax-eligible	4.23%	24
Middle Eastern	3.42%	29
South Asian	3.13%	32
Finnishnot grpmax-eligible	2.61%	38
European (non-Finnish)	2.16%	46

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.Pro241Ser
Coding: c.721C>T
MANE Select: NM_021023
dbSNP: rs138675433
Type: single nucleotide variant
Location: chr1:196790152 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 241: a disulfide bond; the sushi 4 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-pro241ser (accessed [today's date]).

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