Is PRDM12 p.Pro338= (c.1014C>T) pathogenic?

PRDM12 p.Pro338= (c.1014C>T) is classified Likely benign in PRDM12 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-13). Very rare (popmax 0.000421%, nfe); Associated with congenital insensitivity to pain-hypohidrosis syndrome.

What condition is associated with PRDM12 p.Pro338= (c.1014C>T)?

PRDM12 p.Pro338= (c.1014C>T) is associated with congenital insensitivity to pain-hypohidrosis syndrome (ClinVar).

How common is PRDM12 p.Pro338= (c.1014C>T) in the general population?

PRDM12 p.Pro338= (c.1014C>T) is very rare (popmax 0.000421%, nfe) (gnomAD).

PRDM12 p.Pro338=

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.1014C>T · rs1230135786 · VCV1131162

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000421%, nfe)

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	GERP -4.6, phastCons 0.003
Overall
CADD	7.672	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000421% European (non-Finnish) · 4/950,480 alleles

Filtering AF 9.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.6e-05%

Overall 0.000389% 4/1,028,140 alleles · very rare

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.Pro338=
Coding: c.1014C>T
MANE Select: NM_021619
dbSNP: rs1230135786
Type: single nucleotide variant
Location: chr9:130681579 (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.Pro338His Uncertain significance ★ ⚠ same residue
PRDM12 p.Pro338Ser 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

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-pro338 (accessed [today's date]).

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