Is CFH p.Asp966His (c.2896G>C) pathogenic?

CFH p.Asp966His (c.2896G>C) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1842); Very rare (popmax 0.00534%, afr); Associated with Inborn genetic diseases.

What condition is associated with CFH p.Asp966His (c.2896G>C)?

CFH p.Asp966His (c.2896G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CFH p.Asp966His (c.2896G>C) in the general population?

CFH p.Asp966His (c.2896G>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CFH p.Asp966His (c.2896G>C)?

AlphaMissense predicts likely benign (score 0.1842) — an in-silico prediction, not a clinical call.

CFH p.Asp966His

c.2896G>C · rs752629905 · VCV2682689

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1842 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1842	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -7.23	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 -2.6	GERP -1.4
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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,884 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000372% 6/1,613,852 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,721
Admixed American	0.00167%	59,992
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: CFH
Protein: p.Asp966His
Coding: c.2896G>C
MANE Select: NM_000186
dbSNP: rs752629905
Type: single nucleotide variant
Location: chr1:196740732 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 966: the sushi 16 domain; a β-strand; a disulfide bond

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.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
CFH p.Asp947His 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-asp966his (accessed [today's date]).

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