Is CFHR4 p.Glu125Asp (c.375G>T) pathogenic?

CFHR4 p.Glu125Asp (c.375G>T) is classified Benign/Likely benign in CFHR4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.0664); Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CFHR4 p.Glu125Asp (c.375G>T)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

CFHR4 p.Glu125Asp

Q: How common is CFHR4 p.Glu125Asp (c.375G>T) in the general population?

CFHR4 p.Glu125Asp (c.375G>T) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.375G>T · rs10801578 · VCV1232884

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -1.07	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 -2.6	GERP -3.1
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	0.243	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 100% East Asian · 44,690/44,690 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.8%

Overall 99.9% 1,609,298/1,611,274 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	100%	1
Ashkenazi Jewishnot grpmax-eligible	100%	1
Amishnot grpmax-eligible	100%	1
Finnishnot grpmax-eligible	100%	1
European (non-Finnish)	100%	1
South Asian	100%	1
Middle Eastern	99.9%	1
Admixed American	99.8%	1
Remaining individualsnot grpmax-eligible	99.8%	1
African / African-American	97.7%	1

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.Glu125Asp
Coding: c.375G>T
MANE Select: NM_001201550
dbSNP: rs10801578
Type: single nucleotide variant
Location: chr1:196905226 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 125: a disulfide bond; the sushi 2 domain; a UniProt-annotated variant site (in)

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-glu125asp (accessed [today's date]).

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