Is MAP3K6 p.Arg324Trp (c.970C>T) pathogenic?

MAP3K6 p.Arg324Trp (c.970C>T) is classified Uncertain significance in MAP3K6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely pathogenic (0.6784); Ultra-rare (popmax 0.0165%, mid).

How common is MAP3K6 p.Arg324Trp (c.970C>T) in the general population?

MAP3K6 p.Arg324Trp (c.970C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about MAP3K6 p.Arg324Trp (c.970C>T)?

AlphaMissense predicts likely pathogenic (score 0.6784) — an in-silico prediction, not a clinical call.

MAP3K6 p.Arg324Trp

c.970C>T · rs749614171 · VCV3123014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6784 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6784	likely pathogenic
REVEL	0.268	benign-leaning
SaProt	LLR -11.50	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.77, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 11 kb · p 0.00042 · regional, not allelic
Overall
CADD	29.8	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00323% 52/1,611,482 alleles · ultra-rare exomes 48/1,459,272 · genomes 4/152,210 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.011%	9,075
Admixed American	0.00336%	29,790
Remaining individualsnot grpmax-eligible	0.00321%	31,186
European (non-Finnish)	0.00305%	32,740
East Asian	0.00223%	44,838

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.Arg324Trp
Coding: c.970C>T
MANE Select: NM_004672
dbSNP: rs749614171
Type: single nucleotide variant
Location: chr1:27363443 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.36

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

Similar variants

MAP3K6 c.1256-2A>G Likely benign ★★ same type
MAP3K6 c.2915+9A>T Benign ★★ same type
MAP3K6 p.Ala405= Benign/Likely benign ★★ same type
MAP3K6 p.Arg499Cys Benign ★★ same type
MAP3K6 p.Asn622Lys Benign ★★ same type
MAP3K6 p.Gln1142Arg Benign ★★ same type
MAP3K6 p.Glu248= Likely benign ★★ same type
MAP3K6 p.Leu1249= 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-arg324trp (accessed [today's date]).

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