Is CD8A p.Ser229Arg (c.687C>A) pathogenic?

CD8A p.Ser229Arg (c.687C>A) is classified Uncertain significance in CD8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-22). AlphaMissense: likely benign (0.2497); Ultra-rare (popmax 0.024%, nfe); Associated with susceptibility to respiratory infections associated with CD8alpha chain mutation.

How common is CD8A p.Ser229Arg (c.687C>A) in the general population?

CD8A p.Ser229Arg (c.687C>A) is ultra-rare (popmax 0.024%, nfe) (gnomAD).

What do computational predictors say about CD8A p.Ser229Arg (c.687C>A)?

AlphaMissense predicts likely benign (score 0.2497) — an in-silico prediction, not a clinical call.

CD8A p.Ser229Arg

Q: What condition is associated with CD8A p.Ser229Arg (c.687C>A)?

CD8A p.Ser229Arg (c.687C>A) 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.687C>A · rs199807314 · VCV952792

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2497 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

susceptibility to respiratory infections associated with CD8alpha chain mutation

Computational evidence

Protein change
AlphaMissense	0.2497	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.086	GERP -0.61
Regional constraint	o/e 1.13	unconstrained · MANE · 4,902 bp · p 0.024 · regional, not allelic
Overall
CADD	10.38	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% European (non-Finnish) · 283/1,179,622 alleles

Filtering AF 0.0216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0207%

Overall 0.0181% 292/1,613,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.024%	4,168
Remaining individualsnot grpmax-eligible	0.008%	12,498
Finnishnot grpmax-eligible	0.00312%	32,019
Admixed American	0.00167%	60,030
African / African-American	0.00133%	75,024

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.Ser229Arg
Coding: c.687C>A
MANE Select: NM_001768
dbSNP: rs199807314
Type: single nucleotide variant
Location: chr2:86785941 (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 p.Ser229= Likely benign ★ same residue
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

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-ser229arg (accessed [today's date]).

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