Is MAP3K20 p.Ser2Leu (c.5C>T) pathogenic?

MAP3K20 p.Ser2Leu (c.5C>T) is classified Uncertain significance in MAP3K20 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-27). AlphaMissense: likely benign (0.0942); Very rare (popmax 0.00171%, amr).

How common is MAP3K20 p.Ser2Leu (c.5C>T) in the general population?

MAP3K20 p.Ser2Leu (c.5C>T) is very rare (popmax 0.00171%, amr) (gnomAD).

What do computational predictors say about MAP3K20 p.Ser2Leu (c.5C>T)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

MAP3K20 p.Ser2Leu

c.5C>T · rs565333842 · VCV1360457

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -8.08	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 119 kb · p 3.5e-09 · regional, not allelic
Overall
CADD	23.6	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 0.00171% Admixed American · 1/58,522 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00087% 14/1,608,660 alleles · very rare exomes 12/1,456,824 · genomes 2/151,836 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,522
Remaining individualsnot grpmax-eligible	0.00161%	62,164
Finnishnot grpmax-eligible	0.00157%	63,806
European (non-Finnish)	0.000934%	107,106

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: MAP3K20
Protein: p.Ser2Leu
Coding: c.5C>T
MANE Select: NM_016653
dbSNP: rs565333842
Type: single nucleotide variant
Location: chr2:173091036 (GRCh38)
Gene constraint: LOEUF 0.569 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 69.15 · 8 PDB
Residue 2: a modified residue (n-acetylserine); a modified residue (phosphoserine; by autocatalysis)

Full MAP3K20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K20 p.Ser2= Likely benign ★ same residue
MAP3K20 p.Arg250Trp Uncertain significance ★★ ⚠ same type
MAP3K20 p.Arg293Lys Uncertain significance ★★ same type
MAP3K20 p.Arg536Lys Uncertain significance ★★ ⚠ same type
MAP3K20 p.Arg634Gly Uncertain significance ★★ ⚠ same type
MAP3K20 p.Arg774Trp Uncertain significance ★★ ⚠ same type
MAP3K20 p.Arg795His Uncertain significance ★★ ⚠ same type
MAP3K20 p.Gln632Ter 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/map3k20-p-ser2leu (accessed [today's date]).

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