Is CD4 p.Phe123Leu (c.369C>A) pathogenic?

CD4 p.Phe123Leu (c.369C>A) is classified Uncertain significance in CD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-22). AlphaMissense: likely pathogenic (0.9787); Ultra-rare (popmax 0.0217%, amr).

How common is CD4 p.Phe123Leu (c.369C>A) in the general population?

CD4 p.Phe123Leu (c.369C>A) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about CD4 p.Phe123Leu (c.369C>A)?

AlphaMissense predicts likely pathogenic (score 0.9787) — an in-silico prediction, not a clinical call.

CD4 p.Phe123Leu

c.369C>A · rs11064416 · VCV2459148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9787 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9787	likely pathogenic · top 1% in CD4
REVEL	0.169	moderately benign-leaning
SaProt	LLR -10.38	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.35 · evaluated, not missing
Pangolin	Δ0.21	loss · gain 0.19 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -0.047	GERP -2.2, phastCons 0.001
Regional constraint	o/e 0.83	unconstrained · MANE · 19 kb · p 7.9e-05 · regional, not allelic
Overall
CADD	16.59	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 0.0217% Admixed American · 13/59,982 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00103% 15/1,461,302 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,614
European (non-Finnish)	0.00017%	589,838

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.Phe123Leu
Coding: c.369C>A
MANE Select: NM_000616
dbSNP: rs11064416
Type: single nucleotide variant
Location: chr12:6814296 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 84 PDB
Residue 123: the ig-like v-type domain; a β-strand

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

Similar variants

CD4 p.Phe123= Benign ★★ same residue
CD4 p.Ser352Trp Uncertain significance ★★ ⚠ same type
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

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-phe123leu (accessed [today's date]).

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