Is ITPR2 p.Lys1469= (c.4407A>G) pathogenic?

ITPR2 p.Lys1469= (c.4407A>G) is classified Benign in ITPR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-19). Common (popmax 34.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with isolated anhidrosis with normal sweat glands.

What condition is associated with ITPR2 p.Lys1469= (c.4407A>G)?

ITPR2 p.Lys1469= (c.4407A>G) is associated with isolated anhidrosis with normal sweat glands (ClinVar).

ITPR2 p.Lys1469=

Q: How common is ITPR2 p.Lys1469= (c.4407A>G) in the general population?

ITPR2 p.Lys1469= (c.4407A>G) is common (popmax 34.9%, nfe) — 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.4407A>G · rs2230375 · VCV1300046

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 34.9%, nfe) — 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 carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3	GERP -5.4
Overall
CADD	1.476	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 34.9% European (non-Finnish) · 410,050/1,175,316 alleles

Filtering AF 34.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 34.8%

Overall 32.2% 517,403/1,608,204 alleles · common exomes 477,014/1,456,038 · genomes 40,389/152,166 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	39.1%	3
Finnishnot grpmax-eligible	38.4%	3
European (non-Finnish)grpmax	34.9%	3
Remaining individualsnot grpmax-eligible	31.1%	3
Middle Eastern	30.4%	3
South Asian	29.3%	3
Ashkenazi Jewishnot grpmax-eligible	28.2%	4
Admixed American	23.3%	4
African / African-American	11.8%	8
East Asian	7.93%	13

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys1469=
Coding: c.4407A>G
MANE Select: NM_002223
dbSNP: rs2230375
Type: single nucleotide variant
Location: chr12:26580129 (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.Ser685= 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-lys1469 (accessed [today's date]).

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