Is PRDM12 p.Pro345= (c.1035C>T) pathogenic?

PRDM12 p.Pro345= (c.1035C>T) is classified Likely benign in PRDM12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-19). Ultra-rare (popmax 0.088%, sas); Associated with congenital insensitivity to pain-hypohidrosis syndrome.

What condition is associated with PRDM12 p.Pro345= (c.1035C>T)?

PRDM12 p.Pro345= (c.1035C>T) is associated with congenital insensitivity to pain-hypohidrosis syndrome (ClinVar).

How common is PRDM12 p.Pro345= (c.1035C>T) in the general population?

PRDM12 p.Pro345= (c.1035C>T) is ultra-rare (popmax 0.088%, sas) (gnomAD).

PRDM12 p.Pro345=

Q: How is Hereditary sensory and autonomic neuropathy type 8 inherited?

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

c.1035C>T · rs1830903170 · VCV2145918

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.088%, sas)

Conditions

congenital insensitivity to pain-hypohidrosis syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Overall
CADD	12.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.088% South Asian · 19/21,584 alleles

Filtering AF 0.0576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0479%

Overall 0.00214% 21/982,308 alleles · ultra-rare exomes 13/846,666 · genomes 8/135,642 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.088%	1,136
Remaining individualsnot grpmax-eligible	0.00331%	30,250
European (non-Finnish)	0.00012%	830,330

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: PRDM12
Protein: p.Pro345=
Coding: c.1035C>T
MANE Select: NM_021619
dbSNP: rs1830903170
Type: single nucleotide variant
Location: chr9:130681600 (GRCh38)
Gene constraint: LOEUF 1.153 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.81 · 1 PDB

Full PRDM12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital insensitivity to pain-hypohidrosis syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary sensory and autonomic neuropathy type 8 (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

PRDM12 p.Pro345His Uncertain significance ★★ ⚠ same residue
PRDM12 p.Pro345Ala Uncertain significance ★ ⚠ same residue
PRDM12 p.Pro345Leu Uncertain significance ★ ⚠ same residue
PRDM12 p.Pro345_Ala346dup Uncertain significance ★ same residue
PRDM12 p.Pro345_Ala348dup Uncertain significance ★ same residue
PRDM12 p.Ala332Val Uncertain significance ★★ ⚠ same condition
PRDM12 p.Arg147Cys Uncertain significance ★★ same condition
PRDM12 p.Arg147His 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/prdm12-p-pro345 (accessed [today's date]).

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