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

DCD p.Leu66Pro (c.197T>C) is classified Uncertain significance in DCD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: ambiguous (0.4368); Ultra-rare (popmax 0.0133%, amr).

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

DCD p.Leu66Pro (c.197T>C) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

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

AlphaMissense predicts ambiguous (score 0.4368) — an in-silico prediction, not a clinical call.

DCD p.Leu66Pro

c.197T>C · VCV4009695

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4368 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4368	ambiguous
REVEL	0.048	moderately benign-leaning
SaProt	LLR -10.59	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.5	GERP -1.6
Regional constraint	o/e 1.04	unconstrained · MANE · 3,587 bp · p 0.63 · regional, not allelic
Overall
CADD	17.35	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 0.0133% Admixed American · 8/59,992 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00105% 17/1,613,732 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,499
European (non-Finnish)	0.000763%	131,087

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: DCD
Protein: p.Leu66Pro
Coding: c.197T>C
MANE Select: NM_053283
Type: single nucleotide variant
Location: chr12:54645608 (GRCh38)
Gene constraint: LOEUF 1.809 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.88 · 4 PDB
Residue 66: an α-helix; the 'disordered' region

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

Similar variants

DCD p.Asp71Asn Benign ★★ ⚠ same type
DCD p.Asn32Lys Uncertain significance ★ ⚠ same type
DCD p.Asn32Ser Uncertain significance ★ ⚠ same type
DCD p.Asp101Glu Uncertain significance ★ ⚠ same type
DCD p.Glu89Lys Uncertain significance ★ ⚠ same type
DCD p.Glu92Gly Uncertain significance ★ ⚠ same type
DCD p.Gly46Val Uncertain significance ★ ⚠ same type
DCD p.Gly81Arg 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/dcd-p-leu66pro (accessed [today's date]).

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