Is SH2D1A p.Ser63Pro (c.187T>C) pathogenic?

SH2D1A p.Ser63Pro (c.187T>C) is classified Uncertain significance in SH2D1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-10). AlphaMissense: likely pathogenic (0.9625); No allele count reported in gnomAD v4.1 (AN 1,162,122); Associated with X-linked lymphoproliferative disease due to SH2D1A deficiency.

What condition is associated with SH2D1A p.Ser63Pro (c.187T>C)?

SH2D1A p.Ser63Pro (c.187T>C) is associated with X-linked lymphoproliferative disease due to SH2D1A deficiency (ClinVar).

How common is SH2D1A p.Ser63Pro (c.187T>C) in the general population?

SH2D1A p.Ser63Pro (c.187T>C) is no allele count reported in gnomAD v4.1 (AN 1,162,122) (gnomAD).

What do computational predictors say about SH2D1A p.Ser63Pro (c.187T>C)?

AlphaMissense predicts likely pathogenic (score 0.9625) — an in-silico prediction, not a clinical call.

SH2D1A p.Ser63Pro

Q: How is X-linked lymphoproliferative disease due to SAP deficiency inherited?

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

c.187T>C · VCV4735631

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9625 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,162,122)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

X-linked lymphoproliferative disease due to SH2D1A deficiency

Computational evidence

Protein change
AlphaMissense	0.9625	likely pathogenic
REVEL	0.766	pathogenic-leaning
SaProt	LLR -11.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.72 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.52	unconstrained · MANE · 25 kb · p 2.4e-06 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

No allele count reported in gnomAD v4.1 (AN 1,162,122). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SH2D1A
Protein: p.Ser63Pro
Coding: c.187T>C
MANE Select: NM_002351
Type: single nucleotide variant
Location: chrX:124365810 (GRCh38)
Structure: AlphaFold pLDDT 84.53 · 6 PDB
Residue 63: the sh2 domain; a UniProt-annotated variant site (in xlp1; uncertain significance)

Full SH2D1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

X-linked lymphoproliferative disease due to SH2D1A deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For X-linked lymphoproliferative disease due to SAP deficiency (Orphanet):

Inheritance: X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

SH2D1A p.Ser63Cys Uncertain significance ★ ⚠ same residue
SH2D1A c.138-1G>A Pathogenic ★★ same condition
SH2D1A p.Arg55Ter Pathogenic ★★ same condition
SH2D1A p.Asp2Gly Likely pathogenic ★★ ⚠ same condition
SH2D1A p.Met1Thr Pathogenic/Likely pathogenic ★★ same condition
SH2D1A p.Trp64Ter Pathogenic ★★ same condition
SH2D1A p.Cys124Ser Uncertain significance ★★ ⚠ same condition
SH2D1A p.Val102Ile 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/sh2d1a-p-ser63pro (accessed [today's date]).

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