Is NCDN p.Pro533Arg (c.1598C>G) pathogenic?

NCDN p.Pro533Arg (c.1598C>G) is classified Uncertain significance in NCDN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: ambiguous (0.3907); Very rare (popmax 0.000254%, nfe).

How common is NCDN p.Pro533Arg (c.1598C>G) in the general population?

NCDN p.Pro533Arg (c.1598C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about NCDN p.Pro533Arg (c.1598C>G)?

AlphaMissense predicts ambiguous (score 0.3907) — an in-silico prediction, not a clinical call.

NCDN p.Pro533Arg

c.1598C>G · VCV4556269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3907	ambiguous
REVEL	0.772	pathogenic-leaning
SaProt	LLR -9.59	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 3,059 bp · p 6.1e-21 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,520 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,520 alleles · very rare exomes 3/1,461,200 · genomes 0/152,320 · 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: NCDN
Protein: p.Pro533Arg
Coding: c.1598C>G
MANE Select: NM_014284
Type: single nucleotide variant
Location: chr1:35563414 (GRCh38)
Gene constraint: LOEUF 0.261 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.12

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

Similar variants

NCDN p.Pro533Leu Likely pathogenic ★ same residue
NCDN p.Pro533= Likely benign ★ same residue
NCDN p.Arg259Trp Uncertain significance ★★ ⚠ same type
NCDN p.Arg423His Uncertain significance ★★ ⚠ same type
NCDN p.Gly164Ser Uncertain significance ★★ ⚠ same type
NCDN p.Gly189Ser Uncertain significance ★★ ⚠ same type
NCDN p.Arg478Gln Pathogenic ★ ⚠ same type
NCDN p.Glu433Gln Likely pathogenic ★ ⚠ 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/ncdn-p-pro533arg (accessed [today's date]).

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