Is DDN p.Leu91Pro (c.272T>C) pathogenic?

DDN p.Leu91Pro (c.272T>C) is classified Uncertain significance in DDN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: likely pathogenic (0.9096); Very rare (popmax 0.000683%, nfe).

How common is DDN p.Leu91Pro (c.272T>C) in the general population?

DDN p.Leu91Pro (c.272T>C) is very rare (popmax 0.000683%, nfe) (gnomAD).

What do computational predictors say about DDN p.Leu91Pro (c.272T>C)?

AlphaMissense predicts likely pathogenic (score 0.9096) — an in-silico prediction, not a clinical call.

DDN p.Leu91Pro

c.272T>C · rs1176663216 · VCV2327083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9096 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000683%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9096	likely pathogenic · top 6% in DDN
REVEL	0.375	indeterminate
SaProt	LLR -5.01	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,544 bp · p 0.18 · regional, not allelic
Overall
CADD	27.3	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 0.000683% European (non-Finnish) · 8/1,171,712 alleles

Filtering AF 0.000294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.00056% 8/1,429,144 alleles · very rare

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.Leu91Pro
Coding: c.272T>C
MANE Select: NM_015086
dbSNP: rs1176663216
Type: single nucleotide variant
Location: chr12:48998604 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 46.28
Residue 91: the 'disordered' region

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

Similar variants

DDN p.Leu91Gln Uncertain significance ★ ⚠ same residue
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

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-leu91pro (accessed [today's date]).

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