Is MAP3K15 p.Arg554Lys (c.1661G>A) pathogenic?

MAP3K15 p.Arg554Lys (c.1661G>A) is classified Uncertain significance in MAP3K15 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-26). AlphaMissense: likely benign (0.065); Rare (popmax 0.231%, mid).

How common is MAP3K15 p.Arg554Lys (c.1661G>A) in the general population?

MAP3K15 p.Arg554Lys (c.1661G>A) is rare (popmax 0.231%, mid) (gnomAD).

What do computational predictors say about MAP3K15 p.Arg554Lys (c.1661G>A)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

MAP3K15 p.Arg554Lys

c.1661G>A · rs185465571 · VCV2386132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.231%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -5.43	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 -0.037	GERP -3.5, phastCons 0.003
Regional constraint	o/e 1.15	unconstrained · MANE · 155 kb · p 7.9e-07 · regional, not allelic
Overall
CADD	1.153	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 0.231% Middle Eastern · 10/4,331 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0953%

Overall 0.00332% 40/1,205,139 alleles · rare exomes 33/1,093,968 · genomes 7/111,171 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.231%	433
South Asian	0.00714%	13,999
Remaining individualsnot grpmax-eligible	0.00632%	15,814
African / African-American	0.00527%	18,958
Admixed American	0.00441%	22,658
European (non-Finnish)	0.00202%	49,588

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: MAP3K15
Protein: p.Arg554Lys
Coding: c.1661G>A
MANE Select: NM_001001671
dbSNP: rs185465571
Type: single nucleotide variant
Location: chrX:19413394 (GRCh38)
Structure: AlphaFold pLDDT 75.41 · 1 PDB

Full MAP3K15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K15 p.Ala859Thr Uncertain significance ★★ ⚠ same type
MAP3K15 p.Ile295Ser Uncertain significance ★★ ⚠ same type
MAP3K15 p.Leu154Phe Uncertain significance ★★ ⚠ same type
MAP3K15 p.Thr1229Arg Uncertain significance ★★ ⚠ same type
MAP3K15 p.Ser199Asn Benign ★★ same type
MAP3K15 p.Val455Ile Likely benign ★★ same type
PDHA1 c.*1013C>A Benign ★★ same type
PDHA1 c.*1059G>A Benign ★★ 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/map3k15-p-arg554lys (accessed [today's date]).

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