Is ITPR2 p.Met673Val (c.2017A>G) pathogenic?

ITPR2 p.Met673Val (c.2017A>G) is classified Uncertain significance in ITPR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: likely benign (0.0556); Ultra-rare (popmax 0.0132%, sas); Associated with isolated anhidrosis with normal sweat glands.

What condition is associated with ITPR2 p.Met673Val (c.2017A>G)?

ITPR2 p.Met673Val (c.2017A>G) is associated with isolated anhidrosis with normal sweat glands (ClinVar).

How common is ITPR2 p.Met673Val (c.2017A>G) in the general population?

ITPR2 p.Met673Val (c.2017A>G) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about ITPR2 p.Met673Val (c.2017A>G)?

AlphaMissense predicts likely benign (score 0.0556) — an in-silico prediction, not a clinical call.

ITPR2 p.Met673Val

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.2017A>G · VCV3891421

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0556 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Conditions

isolated anhidrosis with normal sweat glands

Computational evidence

Protein change
AlphaMissense	0.0556	likely benign
REVEL	0.295	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 61 kb · p 0.0071 · regional, not allelic
Overall
CADD	18.57	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/90,966 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00594%

Overall 0.00093% 15/1,613,590 alleles · ultra-rare exomes 14/1,461,380 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,581
Remaining individualsnot grpmax-eligible	0.0032%	31,228
European (non-Finnish)	8.48e-05%	1,179,778

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.Met673Val
Coding: c.2017A>G
MANE Select: NM_002223
Type: single nucleotide variant
Location: chr12:26657882 (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.Ser685= Benign ★★ same condition
ITPR2 p.Thr2184Ser Benign/Likely benign ★★ 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-met673val (accessed [today's date]).

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