Is MAP3K19 p.Pro595Arg (c.1784C>G) pathogenic?

MAP3K19 p.Pro595Arg (c.1784C>G) is classified Uncertain significance in MAP3K19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely benign (0.1311); Ultra-rare (popmax 0.0217%, amr).

How common is MAP3K19 p.Pro595Arg (c.1784C>G) in the general population?

MAP3K19 p.Pro595Arg (c.1784C>G) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about MAP3K19 p.Pro595Arg (c.1784C>G)?

AlphaMissense predicts likely benign (score 0.1311) — an in-silico prediction, not a clinical call.

MAP3K19 p.Pro595Arg

c.1784C>G · VCV4051300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1311 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1311	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -6.80	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 5.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 60 kb · p 0.01 · regional, not allelic
Overall
CADD	22.4	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 0.0217% Admixed American · 13/60,022 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000958% 14/1,460,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,617
Remaining individualsnot grpmax-eligible	0.0016%	62,498

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: MAP3K19
Protein: p.Pro595Arg
Coding: c.1784C>G
MANE Select: NM_025052
Type: single nucleotide variant
Location: chr2:134987088 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.13

Full MAP3K19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K19 p.Gln1309His Uncertain significance ★★ ⚠ same type
MAP3K19 p.Ala115Val Uncertain significance ★ ⚠ same type
MAP3K19 p.Ala1214Val Uncertain significance ★ ⚠ same type
MAP3K19 p.Ala1274Val Uncertain significance ★ ⚠ same type
MAP3K19 p.Arg1007Thr Uncertain significance ★ ⚠ same type
MAP3K19 p.Arg1185His Uncertain significance ★ ⚠ same type
MAP3K19 p.Arg1272Gly Uncertain significance ★ same type
MAP3K19 p.Arg1283Gln 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/map3k19-p-pro595arg (accessed [today's date]).

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