Is DECR2 p.Leu66Pro (c.197T>C) pathogenic?

DECR2 p.Leu66Pro (c.197T>C) is classified Uncertain significance in DECR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.6661); Very rare (popmax 0.00339%, nfe).

How common is DECR2 p.Leu66Pro (c.197T>C) in the general population?

DECR2 p.Leu66Pro (c.197T>C) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about DECR2 p.Leu66Pro (c.197T>C)?

AlphaMissense predicts likely pathogenic (score 0.6661) — an in-silico prediction, not a clinical call.

DECR2 p.Leu66Pro

c.197T>C · VCV4659293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6661 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6661	likely pathogenic
REVEL	0.033	moderately benign-leaning
SaProt	LLR -11.07	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -2
Regional constraint	o/e 1.14	unconstrained · MANE · 9,611 bp · p 0.0038 · regional, not allelic
Overall
CADD	8.849	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 0.00339% European (non-Finnish) · 40/1,179,916 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00261% 42/1,607,740 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,498
Remaining individualsnot grpmax-eligible	0.0016%	62,438
African / African-American	0.00133%	74,920

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: DECR2
Protein: p.Leu66Pro
Coding: c.197T>C
MANE Select: NM_020664
Type: single nucleotide variant
Location: chr16:406393 (GRCh38)
Gene constraint: LOEUF 1.731 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.77 · 2 PDB
Residue 66: an α-helix

Full DECR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DECR2 p.Ala124Thr Uncertain significance ★ ⚠ same type
DECR2 p.Ala129Thr Uncertain significance ★ ⚠ same type
DECR2 p.Ala16Val Uncertain significance ★ ⚠ same type
DECR2 p.Ala178Val Uncertain significance ★ ⚠ same type
DECR2 p.Ala187Val Uncertain significance ★ ⚠ same type
DECR2 p.Ala207Thr Uncertain significance ★ ⚠ same type
DECR2 p.Ala246Thr Uncertain significance ★ ⚠ same type
DECR2 p.Ala96Thr 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/decr2-p-leu66pro (accessed [today's date]).

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