Is CFHR4 p.Ser234Thr (c.700T>A) pathogenic?

CFHR4 p.Ser234Thr (c.700T>A) is classified Uncertain significance in CFHR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-25). AlphaMissense: likely benign (0.1793); Ultra-rare (popmax 0.0518%, amr).

How common is CFHR4 p.Ser234Thr (c.700T>A) in the general population?

CFHR4 p.Ser234Thr (c.700T>A) is ultra-rare (popmax 0.0518%, amr) (gnomAD).

What do computational predictors say about CFHR4 p.Ser234Thr (c.700T>A)?

AlphaMissense predicts likely benign (score 0.1793) — an in-silico prediction, not a clinical call.

CFHR4 p.Ser234Thr

c.700T>A · rs749078259 · VCV2357650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1793 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0518%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1793	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -9.96	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 0.51
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	11.0	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 0.0518% Admixed American · 31/59,862 alleles

Filtering AF 0.0375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0326%

Overall 0.0241% 389/1,611,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0518%	1,931
European (non-Finnish)	0.0288%	3,478
Middle Eastern	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.016%	6,244
Finnishnot grpmax-eligible	0.00627%	15,960
African / African-American	0.00404%	24,770
South Asian	0.0011%	91,032

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.Ser234Thr
Coding: c.700T>A
MANE Select: NM_001201550
dbSNP: rs749078259
Type: single nucleotide variant
Location: chr1:196907399 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 234: a disulfide bond; the sushi 4 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-ser234thr (accessed [today's date]).

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