Is NCDN p.Pro656= (c.1968C>T) pathogenic?

NCDN p.Pro656= (c.1968C>T) is classified Likely benign in NCDN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). Ultra-rare (popmax 0.0424%, eas).

How common is NCDN p.Pro656= (c.1968C>T) in the general population?

NCDN p.Pro656= (c.1968C>T) is ultra-rare (popmax 0.0424%, eas) (gnomAD).

NCDN p.Pro656=

c.1968C>T · rs543753358 · VCV2638654

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0424%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -3.7
Overall
CADD	1.303	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0424% East Asian · 19/44,800 alleles

Filtering AF 0.0277% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.023%

Overall 0.0115% 186/1,611,330 alleles · ultra-rare exomes 168/1,458,990 · genomes 18/152,340 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0424%	2,358
Remaining individualsnot grpmax-eligible	0.0225%	4,453
African / African-American	0.0173%	5,772
European (non-Finnish)	0.0115%	8,669
Admixed American	0.00669%	14,948

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.Pro656=
Coding: c.1968C>T
MANE Select: NM_014284
dbSNP: rs543753358
Type: single nucleotide variant
Location: chr1:35565441 (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.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
NCDN p.Pro533Leu Likely pathogenic ★ same type
NCDN p.Pro652Leu 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-pro656 (accessed [today's date]).

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