Is NECAP1 p.Ser65= (c.195A>G) pathogenic?

NECAP1 p.Ser65= (c.195A>G) is classified Uncertain significance in NECAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-16). Ultra-rare (popmax 0.0379%, eas); Associated with developmental and epileptic encephalopathy, 21.

What condition is associated with NECAP1 p.Ser65= (c.195A>G)?

NECAP1 p.Ser65= (c.195A>G) is associated with developmental and epileptic encephalopathy, 21 (ClinVar).

How common is NECAP1 p.Ser65= (c.195A>G) in the general population?

NECAP1 p.Ser65= (c.195A>G) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

NECAP1 p.Ser65=

Q: How is Non-specific early-onset epileptic encephalopathy inherited?

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

c.195A>G · rs770774824 · VCV1439007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Conditions

developmental and epileptic encephalopathy, 21

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 7.8	GERP 1.8, phastCons 1
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0379% East Asian · 17/44,898 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00112% 18/1,612,894 alleles · ultra-rare exomes 17/1,460,670 · genomes 1/152,224 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,641
Admixed American	0.00167%	60,010

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: NECAP1
Protein: p.Ser65=
Coding: c.195A>G
MANE Select: NM_015509
dbSNP: rs770774824
Type: single nucleotide variant
Location: chr12:8090035 (GRCh38)
Gene constraint: LOEUF 0.594 · pLI 0.68 (gnomAD)
Structure: AlphaFold pLDDT 70.78 · 2 PDB
Residue 65: a turn

Full NECAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 21 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific early-onset epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal

Similar variants

NECAP1 p.Ala173Val Uncertain significance ★★ ⚠ same condition
NECAP1 p.Arg102His Uncertain significance ★★ ⚠ same condition
NECAP1 p.Arg146His Uncertain significance ★★ ⚠ same condition
NECAP1 p.Arg46Cys Uncertain significance ★★ ⚠ same condition
NECAP1 p.Asp118Asn Uncertain significance ★★ ⚠ same condition
NECAP1 p.Gly253Glu Uncertain significance ★★ ⚠ same condition
NECAP1 p.Gly45Ala Uncertain significance ★★ ⚠ same condition
NECAP1 p.His126Tyr 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/necap1-p-ser65 (accessed [today's date]).

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