Is MTCL1 p.Arg768Pro (c.2303G>C) pathogenic?

MTCL1 p.Arg768Pro (c.2303G>C) is classified Uncertain significance in MTCL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely pathogenic (0.9029); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MTCL1 p.Arg768Pro (c.2303G>C)?

MTCL1 p.Arg768Pro (c.2303G>C) is associated with Inborn genetic diseases (ClinVar).

How common is MTCL1 p.Arg768Pro (c.2303G>C) in the general population?

MTCL1 p.Arg768Pro (c.2303G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTCL1 p.Arg768Pro (c.2303G>C)?

AlphaMissense predicts likely pathogenic (score 0.9029) — an in-silico prediction, not a clinical call.

MTCL1 p.Arg768Pro

c.2303G>C · VCV4625264

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9029 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9029	likely pathogenic · top 8% in MTCL1
REVEL	0.407	indeterminate
SaProt	LLR -5.54	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 12	GERP 2.2, phastCons 1
Overall
CADD	25.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MTCL1
Protein: p.Arg768Pro
Coding: c.2303G>C
MANE Select: NM_001395333
Type: single nucleotide variant
Location: chr18:8784335 (GRCh38)
Gene constraint: LOEUF 0.663 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.33
Residue 768: the 'disordered' region

Full MTCL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTCL1 p.Arg768Trp Uncertain significance ★ same residue
MTCL1 p.Thr562Ala Uncertain significance ★★ ⚠ same condition
MTCL1 p.Ala964Thr Likely benign ★★ same condition
MTCL1 p.Gly846Ala Likely benign ★★ same condition
MTCL1 p.Ile925Val Likely benign ★★ same condition
MTCL1 c.3939+3A>G Uncertain significance ★ same condition
MTCL1 p.Ala1013Val Uncertain significance ★ same condition
MTCL1 p.Ala1164Val Uncertain significance ★ ⚠ 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/mtcl1-p-arg768pro (accessed [today's date]).

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