Is CD27 p.Met199Thr (c.596T>C) pathogenic?

CD27 p.Met199Thr (c.596T>C) is classified Uncertain significance in CD27 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-09). AlphaMissense: ambiguous (0.3604); Ultra-rare (popmax 0.0506%, afr); Associated with lymphoproliferative syndrome 2.

What condition is associated with CD27 p.Met199Thr (c.596T>C)?

CD27 p.Met199Thr (c.596T>C) is associated with lymphoproliferative syndrome 2 (ClinVar).

How common is CD27 p.Met199Thr (c.596T>C) in the general population?

CD27 p.Met199Thr (c.596T>C) is ultra-rare (popmax 0.0506%, afr) (gnomAD).

What do computational predictors say about CD27 p.Met199Thr (c.596T>C)?

AlphaMissense predicts ambiguous (score 0.3604) — an in-silico prediction, not a clinical call.

CD27 p.Met199Thr

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.596T>C · rs139318215 · VCV2165562

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

lymphoproliferative syndrome 2

Computational evidence

Protein change
AlphaMissense	0.3604	ambiguous
REVEL	0.274	benign-leaning
SaProt	LLR -5.85	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.052, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 6,293 bp · p 0.069 · regional, not allelic
Overall
CADD	17.36	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 0.0506% African / African-American · 38/75,032 alleles

Filtering AF 0.0379% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0334%

Overall 0.0026% 42/1,614,136 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0506%	1,975
Admixed American	0.005%	20,011
South Asian	0.0011%	91,088

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.Met199Thr
Coding: c.596T>C
MANE Select: NM_001242
dbSNP: rs139318215
Type: single nucleotide variant
Location: chr12:6450952 (GRCh38)
Gene constraint: LOEUF 0.946 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.79 · 5 PDB

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-met199thr (accessed [today's date]).

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