Is MAP3K6 p.Arg222Cys (c.664C>T) pathogenic?

MAP3K6 p.Arg222Cys (c.664C>T) is classified Uncertain significance in MAP3K6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely benign (0.1135); Very rare (popmax 0.00668%, eas).

How common is MAP3K6 p.Arg222Cys (c.664C>T) in the general population?

MAP3K6 p.Arg222Cys (c.664C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about MAP3K6 p.Arg222Cys (c.664C>T)?

AlphaMissense predicts likely benign (score 0.1135) — an in-silico prediction, not a clinical call.

MAP3K6 p.Arg222Cys

c.664C>T · VCV4051353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1135	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -8.35	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 6.5	GERP 0.54, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 11 kb · p 0.00042 · regional, not allelic
Overall
CADD	21.2	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 0.00668% East Asian · 3/44,898 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00155% 25/1,612,632 alleles · very rare exomes 22/1,460,414 · genomes 3/152,218 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,966
South Asian	0.0022%	45,533
Admixed American	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,462
Finnishnot grpmax-eligible	0.00159%	62,744
European (non-Finnish)	0.00136%	73,746
African / African-American	0.00133%	74,940

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.Arg222Cys
Coding: c.664C>T
MANE Select: NM_004672
Type: single nucleotide variant
Location: chr1:27364235 (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-arg222cys (accessed [today's date]).

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