Is CFHR1 p.Ala296Val (c.887C>T) pathogenic?

CFHR1 p.Ala296Val (c.887C>T) is classified Likely pathogenic in CFHR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-24). AlphaMissense: likely benign (0.0877); Ultra-rare (popmax 0.0388%, afr).

How common is CFHR1 p.Ala296Val (c.887C>T) in the general population?

CFHR1 p.Ala296Val (c.887C>T) is ultra-rare (popmax 0.0388%, afr) (gnomAD).

What do computational predictors say about CFHR1 p.Ala296Val (c.887C>T)?

AlphaMissense predicts likely benign (score 0.0877) — an in-silico prediction, not a clinical call.

CFHR1 p.Ala296Val

c.887C>T · rs16840561 · VCV1343371

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0877 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0388%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0877	likely benign ⚠ discordant with ClinVar
REVEL	0.039	moderately benign-leaning
SaProt	LLR -3.28	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 0.22	GERP -0.94
Regional constraint	o/e 0.72	unconstrained · MANE · 1,496 bp · p 0.00038 · regional, not allelic
Overall
CADD	4.639	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 0.0388% African / African-American · 22/56,758 alleles

Filtering AF 0.0262% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00322% 49/1,523,612 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0388%	2,580
Middle Eastern	0.0187%	5,352
South Asian	0.015%	6,686
East Asian	0.00448%	22,297
Remaining individualsnot grpmax-eligible	0.0034%	29,450
European (non-Finnish)	0.000885%	112,942

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: CFHR1
Protein: p.Ala296Val
Coding: c.887C>T
MANE Select: NM_002113
dbSNP: rs16840561
Type: single nucleotide variant
Location: chr1:196831893 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.21 · 2 PDB
Residue 296: a disulfide bond; a UniProt-annotated variant site (in); a β-strand; the sushi 5 domain

Full CFHR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR1 p.Asp218Asn Uncertain significance ★★ ⚠ same type
CFHR1 p.Gln44Ter Uncertain significance ★★ same type
CFHR1 p.Ile214Asn Uncertain significance ★★ ⚠ same type
CFHR1 p.Ile70Val Uncertain significance ★★ ⚠ same type
CFHR1 p.Pro223Leu Uncertain significance ★★ ⚠ same type
CFHR1 p.Tyr304Cys Uncertain significance ★★ ⚠ same type
CFHR1 c.253+108G>C Benign ★★ same type
CFHR1 c.253+213G>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/cfhr1-p-ala296val (accessed [today's date]).

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