Is DCT p.Pro42Leu (c.125C>T) pathogenic?

DCT p.Pro42Leu (c.125C>T) is classified Uncertain significance in DCT (ClinVar, Single submitter, 4 submitters). AlphaMissense: ambiguous (0.5446); Ultra-rare (popmax 0.0444%, nfe).

How common is DCT p.Pro42Leu (c.125C>T) in the general population?

DCT p.Pro42Leu (c.125C>T) is ultra-rare (popmax 0.0444%, nfe) (gnomAD).

What do computational predictors say about DCT p.Pro42Leu (c.125C>T)?

AlphaMissense predicts ambiguous (score 0.5446) — an in-silico prediction, not a clinical call.

DCT p.Pro42Leu

c.125C>T · rs140411565 · VCV1210050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5446 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0444%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5446	ambiguous
REVEL	0.907	moderately pathogenic-leaning
SaProt	LLR -9.43	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 39 kb · p 0.21 · 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 0.0444% European (non-Finnish) · 524/1,180,042 alleles

Filtering AF 0.0412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0399%

Overall 0.034% 549/1,614,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0444%	2,252
African / African-American	0.02%	4,996
Remaining individualsnot grpmax-eligible	0.0128%	7,811
Admixed American	0.00333%	30,003

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: DCT
Protein: p.Pro42Leu
Coding: c.125C>T
MANE Select: NM_001922
dbSNP: rs140411565
Type: single nucleotide variant
Location: chr13:94479131 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.33 · 1 PDB

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

Similar variants

DCT p.Arg233Ter Pathogenic/Likely pathogenic ★★ same type
DCT p.Arg275Gln Benign ★★ same type
DCT p.Thr114= Benign ★★ same type
DCT p.Arg326Ter Pathogenic ★ same type
DCT p.Trp71Ter Pathogenic ★ same type
DCT c.1180-2098C>T Uncertain significance ★ same type
DCT c.1180-2111A>G Uncertain significance ★ same type
DCT p.Ala144Thr 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/dct-p-pro42leu (accessed [today's date]).

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