Is CFHR2 p.Pro153Ser (c.457C>T) pathogenic?

CFHR2 p.Pro153Ser (c.457C>T) is classified Uncertain significance in CFHR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-04). AlphaMissense: likely benign (0.229); Very rare (popmax 0.000678%, nfe).

How common is CFHR2 p.Pro153Ser (c.457C>T) in the general population?

CFHR2 p.Pro153Ser (c.457C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about CFHR2 p.Pro153Ser (c.457C>T)?

AlphaMissense predicts likely benign (score 0.229) — an in-silico prediction, not a clinical call.

CFHR2 p.Pro153Ser

c.457C>T · VCV3380425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.229	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -11.29	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 15 kb · p 0.97 · regional, not allelic
Overall
CADD	23.8	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 0.000678% European (non-Finnish) · 8/1,179,226 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,612,640 alleles · very rare

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: CFHR2
Protein: p.Pro153Ser
Coding: c.457C>T
MANE Select: NM_005666
Type: single nucleotide variant
Location: chr1:196957917 (GRCh38)
Gene constraint: LOEUF 1.498 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.90 · 4 PDB
Residue 153: a disulfide bond; an α-helix; the sushi 3 domain

Full CFHR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR2 p.Val16Ala Uncertain significance ★★ ⚠ same type
CFHR2 c.430+141T>A Benign ★★ same type
CFHR2 c.430+20C>T Benign ★★ same type
CFHR2 c.430+7G>A Benign/Likely benign ★★ same type
CFHR2 c.431-48C>A Benign ★★ same type
CFHR2 c.431-65C>T Benign ★★ same type
CFHR2 c.58+129C>G Benign ★★ same type
CFHR2 c.-65C>G 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/cfhr2-p-pro153ser (accessed [today's date]).

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