Is NCAPD2 p.Pro1340Ser (c.4018C>T) pathogenic?

NCAPD2 p.Pro1340Ser (c.4018C>T) is classified Uncertain significance in NCAPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1756); Ultra-rare (popmax 0.04%, afr); Associated with Inborn genetic diseases.

What condition is associated with NCAPD2 p.Pro1340Ser (c.4018C>T)?

NCAPD2 p.Pro1340Ser (c.4018C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NCAPD2 p.Pro1340Ser (c.4018C>T) in the general population?

NCAPD2 p.Pro1340Ser (c.4018C>T) is ultra-rare (popmax 0.04%, afr) (gnomAD).

What do computational predictors say about NCAPD2 p.Pro1340Ser (c.4018C>T)?

AlphaMissense predicts likely benign (score 0.1756) — an in-silico prediction, not a clinical call.

NCAPD2 p.Pro1340Ser

c.4018C>T · rs369464603 · VCV2228290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1756	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -8.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 36 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	24.4	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 0.04% African / African-American · 30/75,038 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00186% 30/1,614,208 alleles · ultra-rare exomes 8/1,461,870 · genomes 22/152,338 · 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: NCAPD2
Protein: p.Pro1340Ser
Coding: c.4018C>T
MANE Select: NM_014865
dbSNP: rs369464603
Type: single nucleotide variant
Location: chr12:6530974 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.94
Residue 1340: the 'disordered' region

Full NCAPD2 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

NCAPD2 p.Pro1340Leu Uncertain significance ★ ⚠ same residue
NCAPD2 c.2735-6C>T Uncertain significance ★★ same condition
NCAPD2 p.Ala43Gly Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Arg1397His Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Arg677His Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Asn598Ile Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Glu1178Lys Uncertain significance ★★ ⚠ same condition
NCAPD2 p.Glu883Lys 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/ncapd2-p-pro1340ser (accessed [today's date]).

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