Is NECAP1 p.Pro236Ser (c.706C>T) pathogenic?

NECAP1 p.Pro236Ser (c.706C>T) is classified Uncertain significance in NECAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-10). AlphaMissense: likely benign (0.065); Ultra-rare (popmax 0.0735%, eas); Associated with Inborn genetic diseases.

What condition is associated with NECAP1 p.Pro236Ser (c.706C>T)?

NECAP1 p.Pro236Ser (c.706C>T) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy, 21 (ClinVar).

How common is NECAP1 p.Pro236Ser (c.706C>T) in the general population?

NECAP1 p.Pro236Ser (c.706C>T) is ultra-rare (popmax 0.0735%, eas) (gnomAD).

What do computational predictors say about NECAP1 p.Pro236Ser (c.706C>T)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

NECAP1 p.Pro236Ser

c.706C>T · rs201797163 · VCV1972958

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0735%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 5.2e-05 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0735% East Asian · 33/44,884 alleles

Filtering AF 0.0538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.047%

Overall 0.00266% 43/1,613,558 alleles · ultra-rare exomes 37/1,461,248 · genomes 6/152,310 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0735%	1,360
African / African-American	0.00933%	10,719
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)	8.48e-05%	1,179,523

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.Pro236Ser
Coding: c.706C>T
MANE Select: NM_015509
dbSNP: rs201797163
Type: single nucleotide variant
Location: chr12:8095630 (GRCh38)
Gene constraint: LOEUF 0.594 · pLI 0.68 (gnomAD)
Structure: AlphaFold pLDDT 70.78 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 21

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-pro236ser (accessed [today's date]).

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