Is CFHR4 p.Leu561Ile (c.1681C>A) pathogenic?

CFHR4 p.Leu561Ile (c.1681C>A) is classified Likely benign in CFHR4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-06). AlphaMissense: likely benign (0.0766); Rare (popmax 0.576%, afr).

How common is CFHR4 p.Leu561Ile (c.1681C>A) in the general population?

CFHR4 p.Leu561Ile (c.1681C>A) is rare (popmax 0.576%, afr) (gnomAD).

What do computational predictors say about CFHR4 p.Leu561Ile (c.1681C>A)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

CFHR4 p.Leu561Ile

c.1681C>A · VCV4684012

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.576%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -5.88	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 -4.9	GERP -2.9
Regional constraint	o/e 1.08	unconstrained · MANE · 193 bp · p 0.5 · regional, not allelic
Overall
CADD	0.19	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 0.576% African / African-American · 429/74,440 alleles

Filtering AF 0.531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.514%

Overall 0.0306% 494/1,612,114 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.576%	174
Remaining individualsnot grpmax-eligible	0.0545%	1,836
Middle Eastern	0.0496%	2,017
Admixed American	0.0384%	2,604
East Asian	0.00447%	22,357
European (non-Finnish)	0.000254%	393,063

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.Leu561Ile
Coding: c.1681C>A
MANE Select: NM_001201550
Type: single nucleotide variant
Location: chr1:196918350 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 561: the sushi 9 domain; a disulfide bond

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

Similar variants

CFHR4 p.Leu561Pro Uncertain significance ★ ⚠ same residue
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

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-leu561ile (accessed [today's date]).

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