Is MAP3K4 p.Pro64Ser (c.190C>T) pathogenic?

MAP3K4 p.Pro64Ser (c.190C>T) is classified Likely benign in MAP3K4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-04). AlphaMissense: likely benign (0.0659); Low-frequency (popmax 1.04%, afr).

How common is MAP3K4 p.Pro64Ser (c.190C>T) in the general population?

MAP3K4 p.Pro64Ser (c.190C>T) is low-frequency (popmax 1.04%, afr) (gnomAD).

What do computational predictors say about MAP3K4 p.Pro64Ser (c.190C>T)?

AlphaMissense predicts likely benign (score 0.0659) — an in-silico prediction, not a clinical call.

MAP3K4 p.Pro64Ser

c.190C>T · VCV3898197

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0659 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.04%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0659	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -5.25	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 1.5	phastCons 0.041
Regional constraint	o/e 1.07	unconstrained · MANE · 57 kb · p 0.27 · regional, not allelic
Overall
CADD	7.119	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 1.04% African / African-American · 783/75,004 alleles

Filtering AF 0.983% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.959%

Overall 0.0563% 909/1,613,788 alleles · low-frequency exomes 479/1,461,544 · genomes 430/152,244 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.04%	96
Remaining individualsnot grpmax-eligible	0.0752%	1,330
Admixed American	0.0633%	1,579
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00339%	29,495

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.Pro64Ser
Coding: c.190C>T
MANE Select: NM_005922
Type: single nucleotide variant
Location: chr6:161034296 (GRCh38)
Gene constraint: LOEUF 0.437 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.66
Residue 64: the 'disordered' region

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

Similar variants

MAP3K4 p.Pro64His Uncertain significance ★ ⚠ same residue
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-pro64ser (accessed [today's date]).

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