Is MAP3K4 p.Pro31Ser (c.91C>T) pathogenic?

MAP3K4 p.Pro31Ser (c.91C>T) is classified Uncertain significance in MAP3K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely benign (0.1138); Ultra-rare (popmax 0.0425%, amr).

How common is MAP3K4 p.Pro31Ser (c.91C>T) in the general population?

MAP3K4 p.Pro31Ser (c.91C>T) is ultra-rare (popmax 0.0425%, amr) (gnomAD).

What do computational predictors say about MAP3K4 p.Pro31Ser (c.91C>T)?

AlphaMissense predicts likely benign (score 0.1138) — an in-silico prediction, not a clinical call.

MAP3K4 p.Pro31Ser

c.91C>T · VCV4549447

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1138 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0425%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1138	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -9.72	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 -0.19	GERP -1.2, phastCons 0.046
Regional constraint	o/e 1.07	unconstrained · MANE · 57 kb · p 0.27 · regional, not allelic
Overall
CADD	12.84	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 0.0425% Admixed American · 23/54,078 alleles

Filtering AF 0.029% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00148% 23/1,555,822 alleles · ultra-rare exomes 22/1,403,658 · genomes 1/152,164 · joint denominator

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: MAP3K4
Protein: p.Pro31Ser
Coding: c.91C>T
MANE Select: NM_005922
Type: single nucleotide variant
Location: chr6:160992022 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.66
Residue 31: the 'disordered' region

Full MAP3K4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K4 p.Pro64Ser Likely benign ★★ same type
MAP3K4 c.3525-1G>A Uncertain significance ★ same type
MAP3K4 c.3674+1G>A Uncertain significance ★ same type
MAP3K4 p.Ala1004Thr Uncertain significance ★ ⚠ same type
MAP3K4 p.Ala1070Ser Uncertain significance ★ ⚠ same type
MAP3K4 p.Ala1105Val Uncertain significance ★ ⚠ same type
MAP3K4 p.Ala1183Thr Uncertain significance ★ ⚠ same type
MAP3K4 p.Ala119Val 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/map3k4-p-pro31ser (accessed [today's date]).

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