Is CFHR4 p.Arg412Trp (c.1234C>T) pathogenic?

CFHR4 p.Arg412Trp (c.1234C>T) is classified Benign/Likely benign in CFHR4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.0662); Low-frequency (popmax 1.1%, afr).

How common is CFHR4 p.Arg412Trp (c.1234C>T) in the general population?

CFHR4 p.Arg412Trp (c.1234C>T) is low-frequency (popmax 1.1%, afr) (gnomAD).

What do computational predictors say about CFHR4 p.Arg412Trp (c.1234C>T)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

CFHR4 p.Arg412Trp

c.1234C>T · VCV4684004

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.1%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -1.72	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 -1.2	GERP -2.4
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	12.87	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 1.1% African / African-American · 817/74,146 alleles

Filtering AF 1.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.01%

Overall 0.0597% 961/1,608,616 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.1%	91
Admixed American	0.111%	901
Remaining individualsnot grpmax-eligible	0.0883%	1,132
Middle Eastern	0.0496%	2,017
South Asian	0.00664%	15,070
European (non-Finnish)	0.00119%	84,121

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.Arg412Trp
Coding: c.1234C>T
MANE Select: NM_001201550
Type: single nucleotide variant
Location: chr1:196914548 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 412: a disulfide bond; the sushi 7 domain

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

Similar variants

CFHR4 p.Arg412= Likely benign ★★ same residue
CFHR4 p.Arg412Gln Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg412trp (accessed [today's date]).

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