Is PRDM12 p.Pro326= (c.978C>T) pathogenic?

PRDM12 p.Pro326= (c.978C>T) is classified Benign in PRDM12 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-03). Common (popmax 52.2%, eas) — too common for a highly-penetrant pathogenic allele; Associated with congenital insensitivity to pain-hypohidrosis syndrome.

What condition is associated with PRDM12 p.Pro326= (c.978C>T)?

PRDM12 p.Pro326= (c.978C>T) is associated with congenital insensitivity to pain-hypohidrosis syndrome (ClinVar).

PRDM12 p.Pro326=

Q: How common is PRDM12 p.Pro326= (c.978C>T) in the general population?

PRDM12 p.Pro326= (c.978C>T) is common (popmax 52.2%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.978C>T · rs12004652 · VCV1165170

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 52.2%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

congenital insensitivity to pain-hypohidrosis syndrome

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 1.2	GERP -0.82, phastCons 1
Overall
CADD	14.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 52.2% East Asian · 17,016/32,576 alleles

Filtering AF 51.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 51.3%

Overall 18.8% 242,701/1,292,826 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	52.2%	2
Admixed American	35.6%	3
African / African-American	34.3%	3
South Asian	33.9%	3
Finnishnot grpmax-eligible	22.4%	4
Remaining individualsnot grpmax-eligible	21.1%	5
European (non-Finnish)	15.4%	6
Ashkenazi Jewishnot grpmax-eligible	15.2%	7
Middle Eastern	15%	7
Amishnot grpmax-eligible	6.17%	16

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.Pro326=
Coding: c.978C>T
MANE Select: NM_021619
dbSNP: rs12004652
Type: single nucleotide variant
Location: chr9:130681543 (GRCh38)
Gene constraint: LOEUF 1.153 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.81 · 1 PDB
Residue 326: the 'disordered' region

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.Pro326Ala 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
PRDM12 p.Arg158Trp Uncertain significance ★★ ⚠ same condition
PRDM12 p.Asn134Ser Uncertain significance ★★ ⚠ same condition
PRDM12 p.Asn141Ser Uncertain significance ★★ ⚠ same condition
PRDM12 p.Asn207Ser 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-pro326 (accessed [today's date]).

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