Is CFHR4 p.Thr328Ile (c.983C>T) pathogenic?

CFHR4 p.Thr328Ile (c.983C>T) is classified Conflicting classifications of pathogenicity in CFHR4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1329); Rare (popmax 0.173%, nfe).

How common is CFHR4 p.Thr328Ile (c.983C>T) in the general population?

CFHR4 p.Thr328Ile (c.983C>T) is rare (popmax 0.173%, nfe) (gnomAD).

What do computational predictors say about CFHR4 p.Thr328Ile (c.983C>T)?

AlphaMissense predicts likely benign (score 0.1329) — an in-silico prediction, not a clinical call.

CFHR4 p.Thr328Ile

c.983C>T · rs200497324 · VCV1285145

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1329 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.173%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1329	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -13	GERP -3.7
Regional constraint	o/e 0.99	unconstrained · MANE · 27 kb · p 0.86 · regional, not allelic
Overall
CADD	9.574	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 0.173% European (non-Finnish) · 2,037/1,178,986 alleles

Filtering AF 0.166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.164%

Overall 0.14% 2,264/1,611,948 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.173%	579
Admixed American	0.104%	966
Remaining individualsnot grpmax-eligible	0.0961%	1,040
South Asian	0.0527%	1,896
Middle Eastern	0.0496%	2,018
African / African-American	0.043%	2,327
Finnishnot grpmax-eligible	0.0345%	2,901

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.Thr328Ile
Coding: c.983C>T
MANE Select: NM_001201550
dbSNP: rs200497324
Type: single nucleotide variant
Location: chr1:196910464 (GRCh38)
Gene constraint: LOEUF 1.204 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.75
Residue 328: a disulfide bond; the sushi 5 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-thr328ile (accessed [today's date]).

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