Is MTCL1 p.Ala751Val (c.2252C>T) pathogenic?

MTCL1 p.Ala751Val (c.2252C>T) is classified Uncertain significance in MTCL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.1027); Rare (popmax 0.167%, eas); Associated with Inborn genetic diseases.

What condition is associated with MTCL1 p.Ala751Val (c.2252C>T)?

MTCL1 p.Ala751Val (c.2252C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MTCL1 p.Ala751Val (c.2252C>T) in the general population?

MTCL1 p.Ala751Val (c.2252C>T) is rare (popmax 0.167%, eas) (gnomAD).

What do computational predictors say about MTCL1 p.Ala751Val (c.2252C>T)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

MTCL1 p.Ala751Val

c.2252C>T · rs199867297 · VCV2387893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.167%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -7.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.95	GERP -2
Overall
CADD	16.26	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.167% East Asian · 74/44,414 alleles

Filtering AF 0.136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.125%

Overall 0.0104% 165/1,589,826 alleles · rare exomes 156/1,437,572 · genomes 9/152,254 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.167%	600
Ashkenazi Jewishnot grpmax-eligible	0.0424%	2,361
Admixed American	0.0373%	2,678
Remaining individualsnot grpmax-eligible	0.00978%	10,228
South Asian	0.00572%	17,493
European (non-Finnish)	0.00395%	25,316

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: MTCL1
Protein: p.Ala751Val
Coding: c.2252C>T
MANE Select: NM_001395333
dbSNP: rs199867297
Type: single nucleotide variant
Location: chr18:8784284 (GRCh38)
Gene constraint: LOEUF 0.663 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.33
Residue 751: 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.Ala751Thr 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-ala751val (accessed [today's date]).

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