Is CD8A p.Leu16Phe (c.46C>T) pathogenic?

CD8A p.Leu16Phe (c.46C>T) is classified Conflicting classifications of pathogenicity in CD8A (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-05). AlphaMissense: likely benign (0.1158); Rare (popmax 0.462%, afr); Associated with susceptibility to respiratory infections associated with CD8alpha chain mutation.

How common is CD8A p.Leu16Phe (c.46C>T) in the general population?

CD8A p.Leu16Phe (c.46C>T) is rare (popmax 0.462%, afr) (gnomAD).

What do computational predictors say about CD8A p.Leu16Phe (c.46C>T)?

AlphaMissense predicts likely benign (score 0.1158) — an in-silico prediction, not a clinical call.

CD8A p.Leu16Phe

Q: What condition is associated with CD8A p.Leu16Phe (c.46C>T)?

CD8A p.Leu16Phe (c.46C>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.46C>T · rs200750291 · VCV720274

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1158 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.462%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

susceptibility to respiratory infections associated with CD8alpha chain mutation

Computational evidence

Protein change
AlphaMissense	0.1158	likely benign
REVEL	0.529	indeterminate
SaProt	LLR -8.88	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.88 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 4,902 bp · p 0.024 · regional, not allelic
Overall
CADD	25.0	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 0.462% African / African-American · 340/73,642 alleles

Filtering AF 0.421% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.405%

Overall 0.0256% 395/1,543,914 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.462%	217
Remaining individualsnot grpmax-eligible	0.045%	2,225
Admixed American	0.0406%	2,460
Middle Eastern	0.0185%	5,418
South Asian	0.00118%	84,538
European (non-Finnish)	0.000435%	229,720

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.Leu16Phe
Coding: c.46C>T
MANE Select: NM_001768
dbSNP: rs200750291
Type: single nucleotide variant
Location: chr2:86790780 (GRCh38)
Gene constraint: LOEUF 1.496 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.03 · 8 PDB

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-leu16phe (accessed [today's date]).

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