Is NCKAP1 p.Ser683Phe (c.2048C>T) pathogenic?

NCKAP1 p.Ser683Phe (c.2048C>T) is classified Uncertain significance in NCKAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-27). AlphaMissense: likely pathogenic (0.8252); Absent from gnomAD v4.1.

How common is NCKAP1 p.Ser683Phe (c.2048C>T) in the general population?

NCKAP1 p.Ser683Phe (c.2048C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NCKAP1 p.Ser683Phe (c.2048C>T)?

AlphaMissense predicts likely pathogenic (score 0.8252) — an in-silico prediction, not a clinical call.

NCKAP1 p.Ser683Phe

c.2048C>T · rs2105826542 · VCV1515703

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8252 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8252	likely pathogenic
REVEL	0.208	benign-leaning
SaProt	LLR -11.12	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 32 kb · p 1.2e-22 · regional, not allelic
Overall
CADD	27.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NCKAP1
Protein: p.Ser683Phe
Coding: c.2048C>T
MANE Select: NM_013436
dbSNP: rs2105826542
Type: single nucleotide variant
Location: chr2:182956567 (GRCh38)
Gene constraint: LOEUF 0.14 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.75 · 5 PDB
Residue 683: an α-helix

Full NCKAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NCKAP1 p.Arg798Ter Pathogenic ★★ same type
NCKAP1 p.Ala1128Val Uncertain significance ★★ ⚠ same type
NCKAP1 p.Arg1054His Uncertain significance ★★ ⚠ same type
NCKAP1 p.Cys327Arg Uncertain significance ★★ ⚠ same type
NCKAP1 p.Glu15Gly Uncertain significance ★★ ⚠ same type
NCKAP1 p.Ile689Val Uncertain significance ★★ ⚠ same type
NCKAP1 p.Leu268Phe Uncertain significance ★★ ⚠ same type
NCKAP1 p.Met665Ile Uncertain significance ★★ ⚠ same type

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-ser683phe (accessed [today's date]).

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