Is MTCL1 p.Pro1620Ser (c.4858C>T) pathogenic?

MTCL1 p.Pro1620Ser (c.4858C>T) is classified Uncertain significance in MTCL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-13). AlphaMissense: likely benign (0.0712); Ultra-rare (popmax 0.016%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MTCL1 p.Pro1620Ser (c.4858C>T)?

MTCL1 p.Pro1620Ser (c.4858C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MTCL1 p.Pro1620Ser (c.4858C>T) in the general population?

MTCL1 p.Pro1620Ser (c.4858C>T) is ultra-rare (popmax 0.016%, nfe) (gnomAD).

What do computational predictors say about MTCL1 p.Pro1620Ser (c.4858C>T)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

MTCL1 p.Pro1620Ser

c.4858C>T · rs200977312 · VCV2351437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -6.26	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 -0.25	GERP -4.4
Overall
CADD	2.531	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1579S vs ClinVar P1620S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% European (non-Finnish) · 184/1,149,054 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0134%

Overall 0.0127% 197/1,546,088 alleles · ultra-rare exomes 187/1,393,916 · genomes 10/152,172 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0202%	4,957
European (non-Finnish)grpmax	0.016%	6,245
African / African-American	0.00138%	72,598

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1620Ser
Coding: c.4858C>T
MANE Select: NM_001395333
dbSNP: rs200977312
Type: single nucleotide variant
Location: chr18:8825288 (GRCh38)
Gene constraint: LOEUF 0.663 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 51.33

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.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
MTCL1 p.Ala1182Thr 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-pro1620ser (accessed [today's date]).

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