Is MAP3K6 p.Phe849fs (c.2544del) pathogenic?

MAP3K6 p.Phe849fs (c.2544del) is classified Likely pathogenic in MAP3K6 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-02-01). Very rare (popmax 0.0061%, nfe).

How common is MAP3K6 p.Phe849fs (c.2544del) in the general population?

MAP3K6 p.Phe849fs (c.2544del) is very rare (popmax 0.0061%, nfe) (gnomAD).

MAP3K6 p.Phe849fs

c.2544del · rs34008139 · VCV806105

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0061%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 19 of 29
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0061% European (non-Finnish) · 72/1,179,972 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00483% 78/1,613,726 alleles · very rare exomes 76/1,461,680 · genomes 2/152,046 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0061%	16,388
East Asian	0.00223%	44,888
Admixed American	0.00167%	59,966
Remaining individualsnot grpmax-eligible	0.0016%	62,474
Finnishnot grpmax-eligible	0.00156%	63,910
African / African-American	0.00134%	74,852
South Asian	0.0011%	91,078

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: MAP3K6
Protein: p.Phe849fs
Coding: c.2544del
MANE Select: NM_004672
dbSNP: rs34008139
Type: Deletion
Location: chr1:27358748 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.36
Residue 849: the protein kinase domain

Full MAP3K6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K6 p.Arg1261fs Uncertain significance ★ same type
MAP3K6 p.Lys1125del 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/map3k6-p-phe849fs (accessed [today's date]).

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