Is PRIMA1 p.Ser140= (c.420G>A) pathogenic?

PRIMA1 p.Ser140= (c.420G>A) is classified Benign in PRIMA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 66.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with PRIMA1 p.Ser140= (c.420G>A)?

PRIMA1 p.Ser140= (c.420G>A) 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.Ser140=

Q: How common is PRIMA1 p.Ser140= (c.420G>A) in the general population?

PRIMA1 p.Ser140= (c.420G>A) is common (popmax 66.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.420G>A · rs1887197 · VCV586377

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 66.9%, 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 -5.7	GERP -3.3
Overall
CADD	0.134	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 66.9% Middle Eastern · 4,047/6,052 alleles

Filtering AF 66.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 66%

Overall 62.8% 1,013,233/1,612,388 alleles · common exomes 924,802/1,460,440 · genomes 88,431/151,948 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	72.5%	1
Middle Easterngrpmax	66.9%	1
Admixed American	66.8%	1
European (non-Finnish)	65.4%	2
Finnishnot grpmax-eligible	63%	2
Amishnot grpmax-eligible	62%	2
Remaining individualsnot grpmax-eligible	61.8%	2
South Asian	55%	2
African / African-American	42.4%	2
East Asian	34.8%	3

Ashkenazi Jewish 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.Ser140=
Coding: c.420G>A
MANE Select: NM_178013
dbSNP: rs1887197
Type: single nucleotide variant
Location: chr14:93721486 (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.Ser140Leu Uncertain significance ★ ⚠ same residue
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

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-ser140 (accessed [today's date]).

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