Is DENR p.Leu32Pro (c.95T>C) pathogenic?

DENR p.Leu32Pro (c.95T>C) is classified Uncertain significance in DENR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-10). AlphaMissense: likely pathogenic (0.6765); Very rare (popmax 0.000509%, nfe).

How common is DENR p.Leu32Pro (c.95T>C) in the general population?

DENR p.Leu32Pro (c.95T>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about DENR p.Leu32Pro (c.95T>C)?

AlphaMissense predicts likely pathogenic (score 0.6765) — an in-silico prediction, not a clinical call.

DENR p.Leu32Pro

c.95T>C · rs376132191 · VCV2482791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6765	likely pathogenic
REVEL	0.368	indeterminate
SaProt	LLR -6.99	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 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 14 kb · p 0.0035 · regional, not allelic
Overall
CADD	25.6	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 0.000509% European (non-Finnish) · 6/1,179,512 alleles

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

Overall 0.000372% 6/1,613,258 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: DENR
Protein: p.Leu32Pro
Coding: c.95T>C
MANE Select: NM_003677
dbSNP: rs376132191
Type: single nucleotide variant
Location: chr12:122753796 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 63.04 · 5 PDB

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

Similar variants

DENR p.Ala21Val Uncertain significance ★ ⚠ same type
DENR p.Asp186Glu Uncertain significance ★ ⚠ same type
DENR p.Asp26Tyr Uncertain significance ★ ⚠ same type
DENR p.Gln96Pro Uncertain significance ★ ⚠ same type
DENR p.Glu77Ala Uncertain significance ★ ⚠ same type
DENR p.Glu89Asp Uncertain significance ★ ⚠ same type
DENR p.Glu89Lys Uncertain significance ★ ⚠ same type
DENR p.Gly194Arg 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/denr-p-leu32pro (accessed [today's date]).

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