Is NCAPD2 p.Arg583Trp (c.1747C>T) pathogenic?

NCAPD2 p.Arg583Trp (c.1747C>T) is classified Uncertain significance in NCAPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: likely benign (0.076); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with NCAPD2 p.Arg583Trp (c.1747C>T)?

NCAPD2 p.Arg583Trp (c.1747C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NCAPD2 p.Arg583Trp (c.1747C>T) in the general population?

NCAPD2 p.Arg583Trp (c.1747C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about NCAPD2 p.Arg583Trp (c.1747C>T)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

NCAPD2 p.Arg583Trp

c.1747C>T · VCV3298691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -8.57	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 5.5	GERP 1.4, phastCons 0.98
Regional constraint	o/e 0.89	unconstrained · MANE · 36 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	20.4	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 0.0329% Middle Eastern · 2/6,078 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00248% 40/1,613,910 alleles · ultra-rare exomes 37/1,461,746 · genomes 3/152,164 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,039
Remaining individualsnot grpmax-eligible	0.0128%	7,809
East Asian	0.0111%	8,980
Admixed American	0.005%	19,995
South Asian	0.00329%	30,358
European (non-Finnish)	0.00161%	62,102

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.Arg583Trp
Coding: c.1747C>T
MANE Select: NM_014865
Type: single nucleotide variant
Location: chr12:6521830 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.94
Residue 583: the 'interactions with smc2 and smc4' region; 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

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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-arg583trp (accessed [today's date]).

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