Is CD27 p.Ala59Thr (c.175G>A) pathogenic?

CD27 p.Ala59Thr (c.175G>A) is classified Benign/Likely benign in CD27 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1051); Common (popmax 28.6%, sas) — too common for a highly-penetrant pathogenic allele; Associated with lymphoproliferative syndrome 2.

What condition is associated with CD27 p.Ala59Thr (c.175G>A)?

CD27 p.Ala59Thr (c.175G>A) is associated with lymphoproliferative syndrome 2 (ClinVar).

What do computational predictors say about CD27 p.Ala59Thr (c.175G>A)?

AlphaMissense predicts likely benign (score 0.1051) — an in-silico prediction, not a clinical call.

CD27 p.Ala59Thr

Q: How common is CD27 p.Ala59Thr (c.175G>A) in the general population?

CD27 p.Ala59Thr (c.175G>A) is common (popmax 28.6%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Combined immunodeficiency due to CD27 deficiency inherited?

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

c.175G>A · rs25680 · VCV1168241

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1051 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 28.6%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphoproliferative syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1051	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -7.91	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 2	GERP 0.23, phastCons 0.48
Regional constraint	o/e 0.90	unconstrained · MANE · 6,293 bp · p 0.069 · regional, not allelic
Overall
CADD	12.14	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 28.6% South Asian · 26,075/91,080 alleles

Filtering AF 28.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.2%

Overall 22% 354,650/1,613,860 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	28.6%	3
European (non-Finnish)	23.5%	4
Remaining individualsnot grpmax-eligible	21.5%	5
Amishnot grpmax-eligible	20.8%	5
Middle Eastern	20.6%	5
Finnishnot grpmax-eligible	17.4%	6
African / African-American	16.8%	6
Ashkenazi Jewishnot grpmax-eligible	15.2%	7
Admixed American	11.2%	9
East Asian	4.23%	24

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: CD27
Protein: p.Ala59Thr
Coding: c.175G>A
MANE Select: NM_001242
dbSNP: rs25680
Type: single nucleotide variant
Location: chr12:6445462 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.79 · 5 PDB
Residue 59: a disulfide bond; a UniProt-annotated variant site (in); an α-helix

Full CD27 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lymphoproliferative syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined immunodeficiency due to CD27 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

CD27 p.Cys53Tyr Pathogenic ★★ same condition
CD27 p.Ala164Pro Uncertain significance ★★ ⚠ same condition
CD27 p.Ala229Thr Uncertain significance ★★ ⚠ same condition
CD27 p.Arg155Thr Uncertain significance ★★ ⚠ same condition
CD27 p.Arg172Gln Uncertain significance ★★ ⚠ same condition
CD27 p.Arg172Gly Uncertain significance ★★ ⚠ same condition
CD27 p.Arg182Ser Uncertain significance ★★ ⚠ same condition
CD27 p.Arg238Lys 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/cd27-p-ala59thr (accessed [today's date]).

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