Is CD8A p.Ser74Phe (c.221C>T) pathogenic?

CD8A p.Ser74Phe (c.221C>T) is classified Uncertain significance in CD8A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-12). AlphaMissense: likely pathogenic (0.7262); Very rare (popmax 0.005%, amr); Associated with susceptibility to respiratory infections associated with CD8alpha chain mutation.

How common is CD8A p.Ser74Phe (c.221C>T) in the general population?

CD8A p.Ser74Phe (c.221C>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CD8A p.Ser74Phe (c.221C>T)?

AlphaMissense predicts likely pathogenic (score 0.7262) — an in-silico prediction, not a clinical call.

CD8A p.Ser74Phe

Q: What condition is associated with CD8A p.Ser74Phe (c.221C>T)?

CD8A p.Ser74Phe (c.221C>T) is associated with susceptibility to respiratory infections associated with CD8alpha chain mutation (ClinVar).

Q: How is Susceptibility to respiratory infections associated with CD8alpha chain mutation inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.221C>T · rs754918271 · VCV1438755

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

susceptibility to respiratory infections associated with CD8alpha chain mutation

Computational evidence

Protein change
AlphaMissense	0.7262	likely pathogenic
REVEL	0.101	moderately benign-leaning
SaProt	LLR -11.29	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -1.3, phastCons 0.94
Regional constraint	o/e 1.13	unconstrained · MANE · 4,902 bp · p 0.024 · regional, not allelic
Overall
CADD	19.51	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 0.005% Admixed American · 3/60,018 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00297% 48/1,614,010 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,006
European (non-Finnish)	0.00373%	26,819
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: CD8A
Protein: p.Ser74Phe
Coding: c.221C>T
MANE Select: NM_001768
dbSNP: rs754918271
Type: single nucleotide variant
Location: chr2:86790510 (GRCh38)
Gene constraint: LOEUF 1.496 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.03 · 8 PDB
Residue 74: a β-strand; the ig-like v-type domain; a disulfide bond

Full CD8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

susceptibility to respiratory infections associated with CD8alpha chain mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Susceptibility to respiratory infections associated with CD8alpha chain mutation (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

CD8A c.403+4C>G Uncertain significance ★★ same condition
CD8A c.626-2A>T Uncertain significance ★★ same condition
CD8A p.Arg165Leu Uncertain significance ★★ ⚠ same condition
CD8A p.Arg165Pro Uncertain significance ★★ ⚠ same condition
CD8A p.His127Tyr Uncertain significance ★★ ⚠ same condition
CD8A p.His208Leu Uncertain significance ★★ ⚠ same condition
CD8A p.Leu10Arg Uncertain significance ★★ ⚠ same condition
CD8A p.Pro130Arg Uncertain significance ★★ ⚠ same condition

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/cd8a-p-ser74phe (accessed [today's date]).

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