Is CFH p.Gln408His (c.1224G>C) pathogenic?

CFH p.Gln408His (c.1224G>C) is classified Uncertain significance in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-09). AlphaMissense: likely pathogenic (0.6261); Very rare (popmax 0.0011%, sas).

How common is CFH p.Gln408His (c.1224G>C) in the general population?

CFH p.Gln408His (c.1224G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CFH p.Gln408His (c.1224G>C)?

AlphaMissense predicts likely pathogenic (score 0.6261) — an in-silico prediction, not a clinical call.

CFH p.Gln408His

c.1224G>C · rs756842126 · VCV2903914

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6261	likely pathogenic
REVEL	0.225	benign-leaning
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.1	GERP -3.8
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	6.656	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 0.0011% South Asian · 1/91,066 alleles

Overall 6.85e-05% 1/1,460,758 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: CFH
Protein: p.Gln408His
Coding: c.1224G>C
MANE Select: NM_000186
dbSNP: rs756842126
Type: single nucleotide variant
Location: chr1:196690127 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 408: a disulfide bond; the sushi 7 domain

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

Similar variants

CFH p.Gln408Ter Pathogenic ★ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same type
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same type
CFH c.2236+1G>C Likely pathogenic ★★ same type
CFH c.3493+1G>A Pathogenic/Likely pathogenic ★★ same type
CFH c.350+1G>T Pathogenic/Likely pathogenic ★★ same type
CFH c.619+1G>A Pathogenic/Likely pathogenic ★★ same type
CFH p.Arg1215Leu Likely pathogenic ★★ ⚠ 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/cfh-p-gln408his (accessed [today's date]).

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