Is CD4 p.Ser352Trp (c.1055C>G) pathogenic?

CD4 p.Ser352Trp (c.1055C>G) is classified Uncertain significance in CD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-30). AlphaMissense: likely benign (0.2276); Ultra-rare (popmax 0.0112%, nfe).

How common is CD4 p.Ser352Trp (c.1055C>G) in the general population?

CD4 p.Ser352Trp (c.1055C>G) is ultra-rare (popmax 0.0112%, nfe) (gnomAD).

What do computational predictors say about CD4 p.Ser352Trp (c.1055C>G)?

AlphaMissense predicts likely benign (score 0.2276) — an in-silico prediction, not a clinical call.

CD4 p.Ser352Trp

c.1055C>G · rs201791740 · VCV2360144

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2276 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2276	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -11.55	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.42	GERP -0.31, phastCons 0.001
Regional constraint	o/e 0.83	unconstrained · MANE · 19 kb · p 7.9e-05 · regional, not allelic
Overall
CADD	18.63	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 0.0112% European (non-Finnish) · 132/1,179,496 alleles

Filtering AF 0.00961% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00837% 135/1,613,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0112%	8,936
Remaining individualsnot grpmax-eligible	0.0032%	31,224
Admixed American	0.00167%	59,882

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: CD4
Protein: p.Ser352Trp
Coding: c.1055C>G
MANE Select: NM_000616
dbSNP: rs201791740
Type: single nucleotide variant
Location: chr12:6817229 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 84 PDB
Residue 352: a disulfide bond; the ig-like c2-type 3 domain

Full CD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD4 p.Thr444Ala Uncertain significance ★★ ⚠ same type
CD4 c.1346+55T>G Benign ★★ same type
CD4 c.49+35A>G Benign ★★ same type
CD4 c.*91C>A Benign ★★ same type
CD4 c.*92A>G Benign ★★ same type
CD4 p.Arg265Trp Benign ★★ ⚠ same type
CD4 p.Arg431Gln Benign/Likely benign ★★ ⚠ same type
CD4 p.Cys447= 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/cd4-p-ser352trp (accessed [today's date]).

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