Is ITPR2 p.Ser685= (c.2055A>G) pathogenic?

ITPR2 p.Ser685= (c.2055A>G) is classified Benign in ITPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-19). Common (popmax 61.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with isolated anhidrosis with normal sweat glands.

What condition is associated with ITPR2 p.Ser685= (c.2055A>G)?

ITPR2 p.Ser685= (c.2055A>G) is associated with isolated anhidrosis with normal sweat glands (ClinVar).

ITPR2 p.Ser685=

Q: How common is ITPR2 p.Ser685= (c.2055A>G) in the general population?

ITPR2 p.Ser685= (c.2055A>G) is common (popmax 61.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Isolated generalized anhidrosis with normal sweat glands inherited?

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

c.2055A>G · rs2291264 · VCV1300050

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 61.5%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

isolated anhidrosis with normal sweat glands

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.46	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -6	GERP -3.2
Overall
CADD	0.298	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 61.5% East Asian · 27,596/44,858 alleles

Filtering AF 60.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 60.7%

Overall 36.5% 589,195/1,613,192 alleles · common exomes 536,810/1,461,084 · genomes 52,385/152,108 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	61.5%	2
Admixed American	52.5%	2
Ashkenazi Jewishnot grpmax-eligible	46.9%	2
Amishnot grpmax-eligible	44.5%	2
South Asian	38.9%	3
Finnishnot grpmax-eligible	37.8%	3
Remaining individualsnot grpmax-eligible	37.1%	3
European (non-Finnish)	35.2%	3
Middle Eastern	29.5%	3
African / African-American	22%	5

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: ITPR2
Protein: p.Ser685=
Coding: c.2055A>G
MANE Select: NM_002223
dbSNP: rs2291264
Type: single nucleotide variant
Location: chr12:26657844 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)

Full ITPR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

isolated anhidrosis with normal sweat glands — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Isolated generalized anhidrosis with normal sweat glands (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

ITPR2 c.3801+23G>A Benign ★★ same condition
ITPR2 c.93-10T>A Benign ★★ same condition
ITPR2 p.Asp1413= Benign ★★ same condition
ITPR2 p.Glu255= Benign ★★ same condition
ITPR2 p.His961= Benign ★★ same condition
ITPR2 p.Lys1469= Benign ★★ same condition
ITPR2 p.Thr2184Ser Benign/Likely benign ★★ same condition
ITPR2 p.Asp632Tyr 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/itpr2-p-ser685 (accessed [today's date]).

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