Is PRIMA1 p.His34= (c.102T>C) pathogenic?

PRIMA1 p.His34= (c.102T>C) is classified Benign in PRIMA1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 78.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with PRIMA1 p.His34= (c.102T>C)?

PRIMA1 p.His34= (c.102T>C) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How is Sleep-related hypermotor epilepsy inherited?

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

PRIMA1 p.His34=

Q: How common is PRIMA1 p.His34= (c.102T>C) in the general population?

PRIMA1 p.His34= (c.102T>C) is common (popmax 78.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.102T>C · rs4905087 · VCV586376

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 78.9%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

familial sleep-related hypermotor epilepsy

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 -3.9	GERP -4.6
Overall
CADD	0.938	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 78.9% Middle Eastern · 4,655/5,898 alleles

Filtering AF 77.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 77.6%

Overall 74.6% 1,153,501/1,546,064 alleles · common exomes 1,046,514/1,394,906 · genomes 106,987/151,158 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	82.3%	1
Finnishnot grpmax-eligible	78.9%	1
Middle Easterngrpmax	78.9%	1
European (non-Finnish)	77.8%	1
Ashkenazi Jewishnot grpmax-eligible	76.8%	1
Remaining individualsnot grpmax-eligible	72.9%	1
Admixed American	63.6%	2
African / African-American	63.2%	2
South Asian	62.5%	2
East Asian	33.8%	3

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: PRIMA1
Protein: p.His34=
Coding: c.102T>C
MANE Select: NM_178013
dbSNP: rs4905087
Type: single nucleotide variant
Location: chr14:93779303 (GRCh38)
Gene constraint: LOEUF 1.053 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 63.74 · 1 PDB

Full PRIMA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial sleep-related hypermotor epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

PRIMA1 p.Arg55Trp Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Asn79Ser Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Gly145Arg Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Ile118Thr Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Leu6Val Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Pro59Leu Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Pro84Ala Uncertain significance ★★ ⚠ same condition
PRIMA1 p.Ser103Phe 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/prima1-p-his34 (accessed [today's date]).

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