Is PRIMA1 p.Ala22= (c.66G>T) pathogenic?

PRIMA1 p.Ala22= (c.66G>T) is classified Likely benign in PRIMA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-17). Very rare (popmax 0.00411%, afr); Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with PRIMA1 p.Ala22= (c.66G>T)?

PRIMA1 p.Ala22= (c.66G>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is PRIMA1 p.Ala22= (c.66G>T) in the general population?

PRIMA1 p.Ala22= (c.66G>T) is very rare (popmax 0.00411%, afr) (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

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

PRIMA1 p.Ala22=

c.66G>T · VCV3664626

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00411%, afr)

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 -1.4	GERP -5.5
Overall
CADD	9.163	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00411% African / African-American · 3/73,060 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000502%

Overall 0.000648% 10/1,542,996 alleles · very rare exomes 8/1,390,752 · genomes 2/152,244 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00411%	24,353
European (non-Finnish)	0.00061%	163,834

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.Ala22=
Coding: c.66G>T
MANE Select: NM_178013
Type: single nucleotide variant
Location: chr14:93787653 (GRCh38)
Gene constraint: LOEUF 1.053 · pLI 0.07 (gnomAD)
Structure: AlphaFold pLDDT 63.74 · 1 PDB
Residue 22: a UniProt-annotated variant site (in a colorectal cancer sample; somatic mutation)

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-ala22 (accessed [today's date]).

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