Is NKAP p.Pro84Ser (c.250C>T) pathogenic?

NKAP p.Pro84Ser (c.250C>T) is classified Uncertain significance in NKAP (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0946); Very rare (popmax 0.00175%, sas); Associated with intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type.

How common is NKAP p.Pro84Ser (c.250C>T) in the general population?

NKAP p.Pro84Ser (c.250C>T) is very rare (popmax 0.00175%, sas) (gnomAD).

What do computational predictors say about NKAP p.Pro84Ser (c.250C>T)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

NKAP p.Pro84Ser

Q: What condition is associated with NKAP p.Pro84Ser (c.250C>T)?

NKAP p.Pro84Ser (c.250C>T) is associated with intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type (ClinVar).

c.250C>T · rs2521710156 · VCV3241991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -4.47	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 2.9	phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 378 bp · p 0.48 · regional, not allelic
Overall
CADD	19.25	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 0.00175% South Asian · 1/57,056 alleles

Overall 8.25e-05% 1/1,212,334 alleles · very rare exomes 1/1,097,945 · genomes 0/114,389 · 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: NKAP
Protein: p.Pro84Ser
Coding: c.250C>T
MANE Select: NM_024528
dbSNP: rs2521710156
Type: single nucleotide variant
Location: chrX:119943356 (GRCh38)
Structure: AlphaFold pLDDT 61.90 · 5 PDB
Residue 84: the 'disordered' region

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

Disease context

intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NKAP p.Arg330His Pathogenic/Likely pathogenic ★★ same condition
NKAP p.Arg333Gln Pathogenic/Likely pathogenic ★★ same condition
NKAP p.Glu271Val Uncertain significance ★★ ⚠ same condition
NKAP p.Lys184Glu Uncertain significance ★★ ⚠ same condition
NKAP p.Lys256Asn Uncertain significance ★★ ⚠ same condition
NKAP p.Pro332Ser Uncertain significance ★★ ⚠ same condition
NKAP c.538+8T>A Benign ★★ same condition
NKAP c.539-17A>T Benign ★★ 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/nkap-p-pro84ser (accessed [today's date]).

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