Is CFHR1 p.Tyr289Phe (c.866A>T) pathogenic?

CFHR1 p.Tyr289Phe (c.866A>T) is classified Uncertain significance in CFHR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.1327); Absent from gnomAD v4.1.

How common is CFHR1 p.Tyr289Phe (c.866A>T) in the general population?

CFHR1 p.Tyr289Phe (c.866A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFHR1 p.Tyr289Phe (c.866A>T)?

AlphaMissense predicts likely benign (score 0.1327) — an in-silico prediction, not a clinical call.

CFHR1 p.Tyr289Phe

c.866A>T · VCV4227315

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1327 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1327	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -9.59	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 1,496 bp · p 0.00038 · regional, not allelic
Overall
CADD	19.33	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CFHR1
Protein: p.Tyr289Phe
Coding: c.866A>T
MANE Select: NM_002113
Type: single nucleotide variant
Location: chr1:196831872 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.21 · 2 PDB
Residue 289: a disulfide bond; 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-tyr289phe (accessed [today's date]).

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