Is NECAP1 p.Pro73Ser (c.217C>T) pathogenic?

NECAP1 p.Pro73Ser (c.217C>T) is classified Uncertain significance in NECAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-25). AlphaMissense: likely pathogenic (0.6663); Very rare (popmax 8.47e-05%, nfe); Associated with developmental and epileptic encephalopathy, 21.

What condition is associated with NECAP1 p.Pro73Ser (c.217C>T)?

NECAP1 p.Pro73Ser (c.217C>T) is associated with developmental and epileptic encephalopathy, 21 (ClinVar).

How common is NECAP1 p.Pro73Ser (c.217C>T) in the general population?

NECAP1 p.Pro73Ser (c.217C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about NECAP1 p.Pro73Ser (c.217C>T)?

AlphaMissense predicts likely pathogenic (score 0.6663) — an in-silico prediction, not a clinical call.

NECAP1 p.Pro73Ser

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.217C>T · rs2120476836 · VCV1505667

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

developmental and epileptic encephalopathy, 21

Computational evidence

Protein change
AlphaMissense	0.6663	likely pathogenic
REVEL	0.419	indeterminate
SaProt	LLR -11.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,020 alleles

Overall 6.2e-05% 1/1,614,146 alleles · very rare exomes 1/1,461,880 · genomes 0/152,266 · joint denominator

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.Pro73Ser
Coding: c.217C>T
MANE Select: NM_015509
dbSNP: rs2120476836
Type: single nucleotide variant
Location: chr12:8090215 (GRCh38)
Gene constraint: LOEUF 0.594 · pLI 0.68 (gnomAD)
Structure: AlphaFold pLDDT 70.78 · 2 PDB
Residue 73: a β-strand

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-pro73ser (accessed [today's date]).

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