Is NCDN p.Pro477Ser (c.1429C>T) pathogenic?

NCDN p.Pro477Ser (c.1429C>T) is classified Uncertain significance in NCDN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-01). AlphaMissense: ambiguous (0.4384); Very rare (popmax 0.000508%, nfe).

How common is NCDN p.Pro477Ser (c.1429C>T) in the general population?

NCDN p.Pro477Ser (c.1429C>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about NCDN p.Pro477Ser (c.1429C>T)?

AlphaMissense predicts ambiguous (score 0.4384) — an in-silico prediction, not a clinical call.

NCDN p.Pro477Ser

c.1429C>T · rs966846201 · VCV3239111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4384	ambiguous
REVEL	0.321	indeterminate
SaProt	LLR -12.29	damaging
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	26.5	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 0.000508% European (non-Finnish) · 6/1,179,974 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,614,076 alleles · very rare exomes 7/1,461,772 · genomes 0/152,304 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)grpmax	0.000508%	196,662

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro477Ser
Coding: c.1429C>T
MANE Select: NM_014284
dbSNP: rs966846201
Type: single nucleotide variant
Location: chr1:35563245 (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-pro477ser (accessed [today's date]).

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