Is MAP3K4 p.Pro86Arg (c.257C>G) pathogenic?

MAP3K4 p.Pro86Arg (c.257C>G) is classified Uncertain significance in MAP3K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely pathogenic (0.6994); Ultra-rare (popmax 0.0483%, sas).

How common is MAP3K4 p.Pro86Arg (c.257C>G) in the general population?

MAP3K4 p.Pro86Arg (c.257C>G) is ultra-rare (popmax 0.0483%, sas) (gnomAD).

What do computational predictors say about MAP3K4 p.Pro86Arg (c.257C>G)?

AlphaMissense predicts likely pathogenic (score 0.6994) — an in-silico prediction, not a clinical call.

MAP3K4 p.Pro86Arg

c.257C>G · rs150383557 · VCV2403654

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6994	likely pathogenic
REVEL	0.624	indeterminate
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 57 kb · p 0.27 · regional, not allelic
Overall
CADD	25.6	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 0.0483% South Asian · 44/91,076 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.0329% 531/1,613,764 alleles · ultra-rare exomes 491/1,461,732 · genomes 40/152,032 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.236%	423
Remaining individualsnot grpmax-eligible	0.0544%	1,838
South Asiangrpmax	0.0483%	2,070
European (non-Finnish)	0.0316%	3,163
Middle Eastern	0.0164%	6,084
Admixed American	0.00667%	14,996
African / African-American	0.00401%	24,953
East Asian	0.00223%	44,870
Finnishnot grpmax-eligible	0.00156%	64,014

Ashkenazi Jewish 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: MAP3K4
Protein: p.Pro86Arg
Coding: c.257C>G
MANE Select: NM_005922
dbSNP: rs150383557
Type: single nucleotide variant
Location: chr6:161034363 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.66
Residue 86: 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-pro86arg (accessed [today's date]).

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