Is CFH p.Glu1135Val (c.3404A>T) pathogenic?

CFH p.Glu1135Val (c.3404A>T) is classified Uncertain significance in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). AlphaMissense: likely benign (0.2789); Very rare (popmax 0.000254%, nfe).

How common is CFH p.Glu1135Val (c.3404A>T) in the general population?

CFH p.Glu1135Val (c.3404A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CFH p.Glu1135Val (c.3404A>T)?

AlphaMissense predicts likely benign (score 0.2789) — an in-silico prediction, not a clinical call.

CFH p.Glu1135Val

c.3404A>T · rs2149118040 · VCV1475788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2789	likely benign
REVEL	0.405	indeterminate
SaProt	LLR -12.33	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.79	GERP 0.61, phastCons 0.001
Regional constraint	o/e 0.66	unconstrained · MANE · 3,752 bp · p 4.7e-06 · regional, not allelic
Overall
CADD	20.2	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 0.000254% European (non-Finnish) · 3/1,180,028 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,866 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.Glu1135Val
Coding: c.3404A>T
MANE Select: NM_000186
dbSNP: rs2149118040
Type: single nucleotide variant
Location: chr1:196745910 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 1135: the sushi 19 domain; a β-strand; a disulfide bond

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

Similar variants

CFH p.Glu1135Asp Uncertain significance ★★ ⚠ same residue
CFH p.Glu1135= Likely benign ★ 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

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-glu1135val (accessed [today's date]).

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