Is CD4 p.Phe227Ser (c.680T>C) pathogenic?

CD4 p.Phe227Ser (c.680T>C) is classified Benign in CD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-06). AlphaMissense: ambiguous (0.3405); Common (popmax 7.12%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CD4 p.Phe227Ser (c.680T>C)?

AlphaMissense predicts ambiguous (score 0.3405) — an in-silico prediction, not a clinical call.

CD4 p.Phe227Ser

Q: How common is CD4 p.Phe227Ser (c.680T>C) in the general population?

CD4 p.Phe227Ser (c.680T>C) is common (popmax 7.12%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.680T>C · rs11064419 · VCV789804

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3405 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.12%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3405	ambiguous
REVEL	0.106	moderately benign-leaning
SaProt	LLR -4.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.34	acceptor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.1	GERP -0.047, phastCons 0.002
Regional constraint	o/e 0.83	unconstrained · MANE · 19 kb · p 7.9e-05 · regional, not allelic
Overall
CADD	18.74	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 7.12% African / African-American · 5,341/75,000 alleles

Filtering AF 6.96% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.9%

Overall 0.402% 6,493/1,614,104 alleles · common exomes 3,354/1,461,878 · genomes 3,139/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.12%	14
Admixed American	0.575%	174
Remaining individualsnot grpmax-eligible	0.474%	211
Middle Eastern	0.297%	337
European (non-Finnish)	0.041%	2,438
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
South Asian	0.00659%	15,179

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.Phe227Ser
Coding: c.680T>C
MANE Select: NM_000616
dbSNP: rs11064419
Type: single nucleotide variant
Location: chr12:6816128 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.35 · 84 PDB
Residue 227: a UniProt-annotated variant site (in); the ig-like c2-type 2 domain

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

Similar variants

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
CD4 p.Arg431Gln 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/cd4-p-phe227ser (accessed [today's date]).

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