Is DDN p.Pro275Ser (c.823C>T) pathogenic?

DDN p.Pro275Ser (c.823C>T) is classified Uncertain significance in DDN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: ambiguous (0.5113); Very rare (popmax 0.00797%, nfe).

How common is DDN p.Pro275Ser (c.823C>T) in the general population?

DDN p.Pro275Ser (c.823C>T) is very rare (popmax 0.00797%, nfe) (gnomAD).

What do computational predictors say about DDN p.Pro275Ser (c.823C>T)?

AlphaMissense predicts ambiguous (score 0.5113) — an in-silico prediction, not a clinical call.

DDN p.Pro275Ser

c.823C>T · rs769036493 · VCV2352617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5113 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00797%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5113	ambiguous
REVEL	0.181	moderately benign-leaning
SaProt	LLR -6.16	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.97, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,544 bp · p 0.18 · regional, not allelic
Overall
CADD	26.3	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 0.00797% European (non-Finnish) · 94/1,180,044 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00613% 99/1,613,776 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00797%	12,554
African / African-American	0.004%	24,982
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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: DDN
Protein: p.Pro275Ser
Coding: c.823C>T
MANE Select: NM_015086
dbSNP: rs769036493
Type: single nucleotide variant
Location: chr12:48998053 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 46.28

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

Similar variants

DDN p.Glu661Gly Benign ★★ same type
DDN p.Pro358Arg Benign ★★ same type
DDN p.Ala154Thr Uncertain significance ★ ⚠ same type
DDN p.Ala169Val Uncertain significance ★ ⚠ same type
DDN p.Ala174Glu Uncertain significance ★ ⚠ same type
DDN p.Ala179Thr Uncertain significance ★ ⚠ same type
DDN p.Ala305Thr Uncertain significance ★ ⚠ same type
DDN p.Ala341Thr Uncertain significance ★ ⚠ 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/ddn-p-pro275ser (accessed [today's date]).

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