Is CFHR4 p.Ile347Val (c.1039A>G) pathogenic?

CFHR4 p.Ile347Val (c.1039A>G) is classified Benign/Likely benign in CFHR4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1039); Low-frequency (popmax 1.07%, afr).

How common is CFHR4 p.Ile347Val (c.1039A>G) in the general population?

CFHR4 p.Ile347Val (c.1039A>G) is low-frequency (popmax 1.07%, afr) (gnomAD).

What do computational predictors say about CFHR4 p.Ile347Val (c.1039A>G)?

AlphaMissense predicts likely benign (score 0.1039) — an in-silico prediction, not a clinical call.

CFHR4 p.Ile347Val

c.1039A>G · VCV4683989

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1039 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.07%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1039	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -10.90	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.2	GERP -3.3
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	0.002	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 1.07% African / African-American · 791/73,974 alleles

Filtering AF 1.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.983%

Overall 0.0574% 918/1,598,454 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.07%	94
Admixed American	0.108%	927
Remaining individualsnot grpmax-eligible	0.0842%	1,187
Middle Eastern	0.0512%	1,953
South Asian	0.00343%	29,150
European (non-Finnish)	0.000426%	234,538

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: CFHR4
Protein: p.Ile347Val
Coding: c.1039A>G
MANE Select: NM_001201550
Type: single nucleotide variant
Location: chr1:196912781 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 347: a disulfide bond; the sushi 6 domain

Full CFHR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFHR4 p.Ala159Val Uncertain significance ★★ ⚠ same type
CFHR4 p.Arg40His Uncertain significance ★★ ⚠ same type
CFHR4 p.Ile318Thr Uncertain significance ★★ ⚠ same type
CFHR4 p.Ser199Tyr Uncertain significance ★★ ⚠ same type
CFHR4 p.Ser507Leu Uncertain significance ★★ ⚠ same type
CFHR4 p.Trp68Ter Uncertain significance ★★ same type
CFHR4 p.Tyr238Ser Uncertain significance ★★ ⚠ same type
CFHR4 c.1180+4A>C Benign/Likely 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/cfhr4-p-ile347val (accessed [today's date]).

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