Is MAP3K20 p.Phe368Cys (c.1103T>G) pathogenic?

MAP3K20 p.Phe368Cys (c.1103T>G) is classified Pathogenic in MAP3K20 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2022-07-28). AlphaMissense: likely pathogenic (0.9257); Absent from gnomAD v4.1; Associated with split-foot malformation-mesoaxial polydactyly syndrome.

How common is MAP3K20 p.Phe368Cys (c.1103T>G) in the general population?

MAP3K20 p.Phe368Cys (c.1103T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MAP3K20 p.Phe368Cys (c.1103T>G)?

AlphaMissense predicts likely pathogenic (score 0.9257) — an in-silico prediction, not a clinical call.

MAP3K20 p.Phe368Cys

Q: What condition is associated with MAP3K20 p.Phe368Cys (c.1103T>G)?

MAP3K20 p.Phe368Cys (c.1103T>G) is associated with split-foot malformation-mesoaxial polydactyly syndrome, split hand-foot malformation 1 (ClinVar).

c.1103T>G · rs863225437 · VCV218144

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9257 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

split-foot malformation-mesoaxial polydactyly syndrome

Computational evidence

Protein change
AlphaMissense	0.9257	likely pathogenic ✓ concordant with ClinVar
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -12.72	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 2.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 23 kb · p 0.75 · regional, not allelic
Overall
CADD	28.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MAP3K20
Protein: p.Phe368Cys
Coding: c.1103T>G
MANE Select: NM_016653
dbSNP: rs863225437
Type: single nucleotide variant
Location: chr2:173232359 (GRCh38)
Gene constraint: LOEUF 0.569 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 69.15 · 8 PDB
Residue 368: the sam domain; a UniProt-annotated variant site (in cnm6; decrease of protein abundance); a UniProt-annotated variant site (in sfmmp; produces protein aggregation)

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

Disease context

split-foot malformation-mesoaxial polydactyly syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: split hand-foot malformation 1

Similar variants

MAP3K20 p.Arg250Trp Uncertain significance ★★ ⚠ same condition
MAP3K20 c.1032+39G>A Benign ★★ same condition
MAP3K20 c.1360-28A>G Benign ★★ same condition
MAP3K20 c.445-37A>G Benign ★★ same condition
MAP3K20 p.Ser531Leu Benign ★★ same condition
MAP3K20 p.Ser531Ter Pathogenic ★ same condition
MAP3K20 p.Cys273Arg Uncertain significance ★ ⚠ same condition
MAP3K20 c.1360-14_1360-9del Benign/Likely benign ★★ 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/map3k20-p-phe368cys (accessed [today's date]).

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