Is MAP3K20 p.Phe253Ser (c.758T>C) pathogenic?

MAP3K20 p.Phe253Ser (c.758T>C) is classified Likely benign in MAP3K20 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-02). AlphaMissense: likely pathogenic (0.9779); Rare (popmax 0.421%, sas).

How common is MAP3K20 p.Phe253Ser (c.758T>C) in the general population?

MAP3K20 p.Phe253Ser (c.758T>C) is rare (popmax 0.421%, sas) (gnomAD).

What do computational predictors say about MAP3K20 p.Phe253Ser (c.758T>C)?

AlphaMissense predicts likely pathogenic (score 0.9779) — an in-silico prediction, not a clinical call.

MAP3K20 p.Phe253Ser

c.758T>C · rs376675527 · VCV1593094

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9779 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.421%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9779	likely pathogenic
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -15.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 23 kb · p 0.75 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.421% South Asian · 376/89,338 alleles

Filtering AF 0.386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.372%

Overall 0.0318% 511/1,606,616 alleles · rare exomes 473/1,454,260 · genomes 38/152,356 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.421%	238
Middle Eastern	0.166%	602
Remaining individualsnot grpmax-eligible	0.0321%	3,112
Admixed American	0.0155%	6,459
European (non-Finnish)	0.00773%	12,938
African / African-American	0.00402%	24,894
East Asian	0.00223%	44,808
Finnishnot grpmax-eligible	0.00156%	63,964

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.Phe253Ser
Coding: c.758T>C
MANE Select: NM_016653
dbSNP: rs376675527
Type: single nucleotide variant
Location: chr2:173209742 (GRCh38)
Gene constraint: LOEUF 0.569 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 69.15 · 8 PDB
Residue 253: the protein kinase domain; a UniProt-annotated variant site (in cnm6; decrease of protein abundance); an α-helix

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

Similar variants

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
MAP3K20 p.Glu405Gly 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-phe253ser (accessed [today's date]).

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