Is PRDM12 p.Ser73= (c.219C>T) pathogenic?

PRDM12 p.Ser73= (c.219C>T) is classified Likely benign in PRDM12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-23). Very rare (popmax 0.0028%, nfe); Associated with congenital insensitivity to pain-hypohidrosis syndrome.

What condition is associated with PRDM12 p.Ser73= (c.219C>T)?

PRDM12 p.Ser73= (c.219C>T) is associated with congenital insensitivity to pain-hypohidrosis syndrome (ClinVar).

How common is PRDM12 p.Ser73= (c.219C>T) in the general population?

PRDM12 p.Ser73= (c.219C>T) is very rare (popmax 0.0028%, nfe) (gnomAD).

PRDM12 p.Ser73=

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.219C>T · rs778954222 · VCV1175445

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0028%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9.3	GERP -3.8
Overall
CADD	1.208	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 32/1,141,046 alleles

Filtering AF 0.00203% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00174%

Overall 0.00221% 34/1,537,016 alleles · very rare exomes 32/1,384,816 · genomes 2/152,200 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,658
Remaining individualsnot grpmax-eligible	0.00168%	59,396
South Asian	0.0012%	83,434

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.Ser73=
Coding: c.219C>T
MANE Select: NM_021619
dbSNP: rs778954222
Type: single nucleotide variant
Location: chr9:130664872 (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.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
PRDM12 p.Asn277Lys 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-ser73 (accessed [today's date]).

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