Is MTCL3 p.Pro216Ser (c.646C>T) pathogenic?

MTCL3 p.Pro216Ser (c.646C>T) is classified Uncertain significance in MTCL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: likely benign (0.057); Very rare (popmax 0.00449%, eas).

How common is MTCL3 p.Pro216Ser (c.646C>T) in the general population?

MTCL3 p.Pro216Ser (c.646C>T) is very rare (popmax 0.00449%, eas) (gnomAD).

What do computational predictors say about MTCL3 p.Pro216Ser (c.646C>T)?

AlphaMissense predicts likely benign (score 0.057) — an in-silico prediction, not a clinical call.

MTCL3 p.Pro216Ser

c.646C>T · VCV3296563

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.057 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00449%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.057	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -5.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.8, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 1,092 bp · p 0.2 · regional, not allelic
Overall
CADD	18.68	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 0.00449% East Asian · 2/44,572 alleles

Filtering AF 0.000744% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.00025% 4/1,602,036 alleles · very rare exomes 4/1,450,898 · genomes 0/151,138 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00449%	22,286
European (non-Finnish)	0.00017%	589,175

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.Pro216Ser
Coding: c.646C>T
MANE Select: NM_001400265
Type: single nucleotide variant
Location: chr6:127515969 (GRCh38)
Structure: AlphaFold pLDDT 66.58
Residue 216: the 'disordered' region

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-pro216ser (accessed [today's date]).

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