Is CFH p.Ile685Phe (c.2053A>T) pathogenic?

CFH p.Ile685Phe (c.2053A>T) is classified Uncertain significance in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely benign (0.1191); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CFH p.Ile685Phe (c.2053A>T)?

CFH p.Ile685Phe (c.2053A>T) is associated with Inborn genetic diseases (ClinVar).

How common is CFH p.Ile685Phe (c.2053A>T) in the general population?

CFH p.Ile685Phe (c.2053A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CFH p.Ile685Phe (c.2053A>T)?

AlphaMissense predicts likely benign (score 0.1191) — an in-silico prediction, not a clinical call.

CFH p.Ile685Phe

c.2053A>T · VCV3266591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1191 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1191	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	—	withheld · numbering disagrees past residue 402 · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.21	donor loss, 7 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -1.5	GERP -3.7
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	13.33	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 is an independent agreement signal.

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: CFH
Protein: p.Ile685Phe
Coding: c.2053A>T
MANE Select: NM_000186
Type: single nucleotide variant
Location: chr1:196726649 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 685: the sushi 11 domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFH p.Ile685Thr Uncertain significance ★★ same residue
CFH p.Ala421Thr Uncertain significance ★★ ⚠ same condition
CFH p.Arg53Leu Uncertain significance ★★ same condition
CFH p.Asn1050Ile Uncertain significance ★★ ⚠ same condition
CFH p.Asn660His Uncertain significance ★★ ⚠ same condition
CFH p.Asn75His Uncertain significance ★★ ⚠ same condition
CFH p.Asp276Glu Uncertain significance ★★ ⚠ same condition
CFH p.Asp855Asn Uncertain significance ★★ ⚠ same condition

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-ile685phe (accessed [today's date]).

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