Is MTCL3 p.Ala424Asp (c.1271C>A) pathogenic?

MTCL3 p.Ala424Asp (c.1271C>A) is classified Uncertain significance in MTCL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30). AlphaMissense: likely pathogenic (0.9388); Very rare (popmax 0.0011%, nfe).

How common is MTCL3 p.Ala424Asp (c.1271C>A) in the general population?

MTCL3 p.Ala424Asp (c.1271C>A) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about MTCL3 p.Ala424Asp (c.1271C>A)?

AlphaMissense predicts likely pathogenic (score 0.9388) — an in-silico prediction, not a clinical call.

MTCL3 p.Ala424Asp

c.1271C>A · VCV3399267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9388 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9388	likely pathogenic
REVEL	0.538	indeterminate
SaProt	LLR -11.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 39 kb · p 5.1e-05 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% European (non-Finnish) · 13/1,180,034 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,614,092 alleles · very rare exomes 13/1,461,760 · genomes 0/152,332 · joint denominator

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: MTCL3
Protein: p.Ala424Asp
Coding: c.1271C>A
MANE Select: NM_001400265
Type: single nucleotide variant
Location: chr6:127514878 (GRCh38)
Structure: AlphaFold pLDDT 66.58

Full MTCL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTCL3 p.Ala102Val Uncertain significance ★ ⚠ same type
MTCL3 p.Ala109Glu Uncertain significance ★ ⚠ same type
MTCL3 p.Ala113Val Uncertain significance ★ ⚠ same type
MTCL3 p.Ala117Ser Uncertain significance ★ ⚠ same type
MTCL3 p.Ala239Glu Uncertain significance ★ ⚠ same type
MTCL3 p.Ala270Val Uncertain significance ★ ⚠ same type
MTCL3 p.Ala304Thr Uncertain significance ★ ⚠ same type
MTCL3 p.Ala313Val 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/mtcl3-p-ala424asp (accessed [today's date]).

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