Is SH2D1A p.Arg75= (c.225A>G) pathogenic?

SH2D1A p.Arg75= (c.225A>G) is classified Conflicting classifications of pathogenicity in SH2D1A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-03). Very rare (popmax 0.00526%, afr); Associated with X-linked lymphoproliferative disease due to SH2D1A deficiency.

What condition is associated with SH2D1A p.Arg75= (c.225A>G)?

SH2D1A p.Arg75= (c.225A>G) is associated with X-linked lymphoproliferative disease due to SH2D1A deficiency (ClinVar).

How common is SH2D1A p.Arg75= (c.225A>G) in the general population?

SH2D1A p.Arg75= (c.225A>G) is very rare (popmax 0.00526%, afr) (gnomAD).

SH2D1A p.Arg75=

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.225A>G · rs371553659 · VCV1313738

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00526%, afr)

Conditions

X-linked lymphoproliferative disease due to SH2D1A deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 1, phastCons 1
Overall
CADD	10.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00526% African / African-American · 3/57,054 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000687%

Overall 0.000249% 3/1,202,565 alleles · very rare exomes 0/1,090,544 · genomes 3/112,021 · joint denominator

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: SH2D1A
Protein: p.Arg75=
Coding: c.225A>G
MANE Select: NM_002351
dbSNP: rs371553659
Type: single nucleotide variant
Location: chrX:124370199 (GRCh38)
Structure: AlphaFold pLDDT 84.53 · 6 PDB
Residue 75: the sh2 domain; the 'interaction with fyn sh3 domain' region; a UniProt-annotated variant site (in xlp1; uncertain significance); an α-helix

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 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.Ser63Pro 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-arg75 (accessed [today's date]).

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