Is NCKAP1 p.Pro249Ser (c.745C>T) pathogenic?

NCKAP1 p.Pro249Ser (c.745C>T) is classified Uncertain significance in NCKAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-16). AlphaMissense: likely pathogenic (0.5957); Very rare (popmax 0.000171%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NCKAP1 p.Pro249Ser (c.745C>T)?

NCKAP1 p.Pro249Ser (c.745C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NCKAP1 p.Pro249Ser (c.745C>T) in the general population?

NCKAP1 p.Pro249Ser (c.745C>T) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about NCKAP1 p.Pro249Ser (c.745C>T)?

AlphaMissense predicts likely pathogenic (score 0.5957) — an in-silico prediction, not a clinical call.

NCKAP1 p.Pro249Ser

c.745C>T · rs2468666563 · VCV2336051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5957	likely pathogenic
REVEL	0.335	indeterminate
SaProt	LLR -2.72	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 81 kb · p 2.6e-11 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000171% European (non-Finnish) · 2/1,170,532 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000138% 2/1,450,638 alleles · very rare

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: NCKAP1
Protein: p.Pro249Ser
Coding: c.745C>T
MANE Select: NM_013436
dbSNP: rs2468666563
Type: single nucleotide variant
Location: chr2:182994884 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.75 · 5 PDB
Residue 249: an α-helix

Full NCKAP1 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

Similar variants

NCKAP1 p.Arg1054His Uncertain significance ★★ ⚠ same condition
NCKAP1 p.Cys327Arg Uncertain significance ★★ ⚠ same condition
NCKAP1 p.Glu15Gly Uncertain significance ★★ ⚠ same condition
NCKAP1 p.Ile689Val Uncertain significance ★★ ⚠ same condition
NCKAP1 p.Leu268Phe Uncertain significance ★★ ⚠ same condition
NCKAP1 p.Met665Ile Uncertain significance ★★ ⚠ same condition
NCKAP1 p.Met695Ile Uncertain significance ★★ ⚠ same condition
NCKAP1 p.Val431Leu 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/nckap1-p-pro249ser (accessed [today's date]).

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