Is NCAPD2 p.Pro497Arg (c.1490C>G) pathogenic?

NCAPD2 p.Pro497Arg (c.1490C>G) is classified Uncertain significance in NCAPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.1123); Ultra-rare (popmax 0.08%, afr); Associated with Inborn genetic diseases.

What condition is associated with NCAPD2 p.Pro497Arg (c.1490C>G)?

NCAPD2 p.Pro497Arg (c.1490C>G) is associated with Inborn genetic diseases (ClinVar).

How common is NCAPD2 p.Pro497Arg (c.1490C>G) in the general population?

NCAPD2 p.Pro497Arg (c.1490C>G) is ultra-rare (popmax 0.08%, afr) (gnomAD).

What do computational predictors say about NCAPD2 p.Pro497Arg (c.1490C>G)?

AlphaMissense predicts likely benign (score 0.1123) — an in-silico prediction, not a clinical call.

NCAPD2 p.Pro497Arg

c.1490C>G · rs150719071 · VCV2509534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1123 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1123	likely benign
REVEL	0.115	moderately benign-leaning
SaProt	LLR -8.99	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 4.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 36 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	18.29	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 0.08% African / African-American · 60/75,026 alleles

Filtering AF 0.0637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0579%

Overall 0.00403% 65/1,614,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.08%	1,250
Admixed American	0.00833%	12,002

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.Pro497Arg
Coding: c.1490C>G
MANE Select: NM_014865
dbSNP: rs150719071
Type: single nucleotide variant
Location: chr12:6517860 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.94
Residue 497: the 'interactions with smc2 and smc4' 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 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
NCAPD2 c.2482-6C>T 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-pro497arg (accessed [today's date]).

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