Is CD247 p.Arg133Trp (c.397C>T) pathogenic?

CD247 p.Arg133Trp (c.397C>T) is classified Uncertain significance in CD247 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-20). AlphaMissense: ambiguous (0.345); Ultra-rare (popmax 0.0911%, sas); Associated with immunodeficiency 25.

What condition is associated with CD247 p.Arg133Trp (c.397C>T)?

CD247 p.Arg133Trp (c.397C>T) is associated with immunodeficiency 25 (ClinVar).

How common is CD247 p.Arg133Trp (c.397C>T) in the general population?

CD247 p.Arg133Trp (c.397C>T) is ultra-rare (popmax 0.0911%, sas) (gnomAD).

What do computational predictors say about CD247 p.Arg133Trp (c.397C>T)?

AlphaMissense predicts ambiguous (score 0.345) — an in-silico prediction, not a clinical call.

CD247 p.Arg133Trp

Q: How is T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta inherited?

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

c.397C>T · rs751981677 · VCV1057409

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.345 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0911%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

immunodeficiency 25

Computational evidence

Protein change
AlphaMissense	0.345	ambiguous
REVEL	0.675	pathogenic-leaning
SaProt	LLR -13.04	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.23	donor loss, 32 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 87 kb · p 0.18 · regional, not allelic
Overall
CADD	32.0	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 0.0911% South Asian · 83/91,082 alleles

Filtering AF 0.0752% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0694%

Overall 0.00675% 109/1,614,198 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0911%	1,097
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0048%	20,836
East Asian	0.00446%	22,439
Finnishnot grpmax-eligible	0.00156%	64,036
African / African-American	0.00133%	75,064
European (non-Finnish)	0.00127%	78,668

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: CD247
Protein: p.Arg133Trp
Coding: c.397C>T
MANE Select: NM_198053
dbSNP: rs751981677
Type: single nucleotide variant
Location: chr1:167433056 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.66 (gnomAD)
Structure: AlphaFold pLDDT 62.36 · 38 PDB
Residue 133: the itam 3 domain; the 'disordered' region

Full CD247 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 25 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CD247 p.Arg133Gln Uncertain significance ★★ ⚠ same residue
CD247 p.Gln101Ter Pathogenic/Likely pathogenic ★★ same condition
CD247 c.58+6G>T Uncertain significance ★★ same condition
CD247 p.Ala120Val Uncertain significance ★★ ⚠ same condition
CD247 p.Ala63Pro Uncertain significance ★★ ⚠ same condition
CD247 p.Ala9Thr Uncertain significance ★★ ⚠ same condition
CD247 p.Arg103Lys Uncertain significance ★★ ⚠ same condition
CD247 p.Arg132Cys 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/cd247-p-arg133trp (accessed [today's date]).

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