Is CFHR4 p.Arg40His (c.119G>A) pathogenic?

CFHR4 p.Arg40His (c.119G>A) is classified Uncertain significance in CFHR4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-15). AlphaMissense: likely benign (0.1696); Ultra-rare (popmax 0.0709%, nfe).

How common is CFHR4 p.Arg40His (c.119G>A) in the general population?

CFHR4 p.Arg40His (c.119G>A) is ultra-rare (popmax 0.0709%, nfe) (gnomAD).

What do computational predictors say about CFHR4 p.Arg40His (c.119G>A)?

AlphaMissense predicts likely benign (score 0.1696) — an in-silico prediction, not a clinical call.

CFHR4 p.Arg40His

c.119G>A · rs200977143 · VCV827994

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0709%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1696	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -9.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.4	GERP 0.57
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	5.361	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 0.0709% European (non-Finnish) · 836/1,178,858 alleles

Filtering AF 0.0669% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0653%

Overall 0.0584% 942/1,611,832 alleles · ultra-rare exomes 878/1,460,380 · genomes 64/151,452 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0709%	1,410
African / African-American	0.0484%	2,068
Remaining individualsnot grpmax-eligible	0.0304%	3,285
Finnishnot grpmax-eligible	0.0282%	3,547
South Asian	0.0264%	3,792
Admixed American	0.0134%	7,486
East Asian	0.00223%	44,808

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.Arg40His
Coding: c.119G>A
MANE Select: NM_001201550
dbSNP: rs200977143
Type: single nucleotide variant
Location: chr1:196902478 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 40: the sushi 1 domain

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

Similar variants

CFHR4 p.Arg40Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CFHR4 p.Ala159Val 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-arg40his (accessed [today's date]).

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