Is CDT1 p.Met375Ile (c.1125G>A) pathogenic?

CDT1 p.Met375Ile (c.1125G>A) is classified Uncertain significance in CDT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-24). AlphaMissense: likely pathogenic (0.7932); Ultra-rare (popmax 0.0178%, eas); Associated with Meier-Gorlin syndrome 4.

What condition is associated with CDT1 p.Met375Ile (c.1125G>A)?

CDT1 p.Met375Ile (c.1125G>A) is associated with Meier-Gorlin syndrome 4 (ClinVar).

How common is CDT1 p.Met375Ile (c.1125G>A) in the general population?

CDT1 p.Met375Ile (c.1125G>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about CDT1 p.Met375Ile (c.1125G>A)?

AlphaMissense predicts likely pathogenic (score 0.7932) — an in-silico prediction, not a clinical call.

CDT1 p.Met375Ile

c.1125G>A · rs779105998 · VCV1029984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Meier-Gorlin syndrome 4

Computational evidence

Protein change
AlphaMissense	0.7932	likely pathogenic · top 7% in CDT1
REVEL	0.285	benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.50	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 4,443 bp · p 1.2e-07 · regional, not allelic
Overall
CADD	33.0	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 0.0178% East Asian · 8/44,894 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,612,762 alleles · ultra-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: CDT1
Protein: p.Met375Ile
Coding: c.1125G>A
MANE Select: NM_030928
dbSNP: rs779105998
Type: single nucleotide variant
Location: chr16:88807053 (GRCh38)
Gene constraint: LOEUF 1.737 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.51 · 6 PDB

Full CDT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Meier-Gorlin syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDT1 c.832+1G>A Pathogenic/Likely pathogenic ★★ same condition
CDT1 p.Arg462Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
CDT1 p.Arg250Cys Uncertain significance ★★ ⚠ same condition
CDT1 p.Gly281Arg Uncertain significance ★★ ⚠ same condition
CDT1 p.Val204Met Uncertain significance ★★ same condition
CDT1 p.Cys234Arg Benign ★★ same condition
CDT1 p.His305= Benign ★★ same condition
CDT1 p.Leu529= Benign ★★ same condition

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/cdt1-p-met375ile (accessed [today's date]).

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