Is MAP2K6 p.Ser326Phe (c.977C>T) pathogenic?

MAP2K6 p.Ser326Phe (c.977C>T) is classified Uncertain significance in MAP2K6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.1702); Ultra-rare (popmax 0.0168%, nfe).

How common is MAP2K6 p.Ser326Phe (c.977C>T) in the general population?

MAP2K6 p.Ser326Phe (c.977C>T) is ultra-rare (popmax 0.0168%, nfe) (gnomAD).

What do computational predictors say about MAP2K6 p.Ser326Phe (c.977C>T)?

AlphaMissense predicts likely benign (score 0.1702) — an in-silico prediction, not a clinical call.

MAP2K6 p.Ser326Phe

c.977C>T · VCV4103146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1702	likely benign
REVEL	0.463	indeterminate
SaProt	LLR -12.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 15 kb · p 0.052 · regional, not allelic
Overall
CADD	25.9	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 0.0168% European (non-Finnish) · 198/1,179,082 alleles

Filtering AF 0.0149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.0128% 207/1,612,764 alleles · ultra-rare exomes 198/1,460,458 · genomes 9/152,306 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0168%	5,955
Remaining individualsnot grpmax-eligible	0.00801%	12,485
African / African-American	0.00533%	18,752

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: MAP2K6
Protein: p.Ser326Phe
Coding: c.977C>T
MANE Select: NM_002758
Type: single nucleotide variant
Location: chr17:69541725 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI 0.58 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 9 PDB
Residue 326: the 'dvd domain' region; an α-helix

Full MAP2K6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K6 p.Ala189Asp Uncertain significance ★ ⚠ same type
MAP2K6 p.Arg254Gln Uncertain significance ★ ⚠ same type
MAP2K6 p.Glu167Ala Uncertain significance ★ ⚠ same type
MAP2K6 p.Gly147Val Uncertain significance ★ ⚠ same type
MAP2K6 p.Ile144Val Uncertain significance ★ ⚠ same type
MAP2K6 p.Ile39Val Uncertain significance ★ ⚠ same type
MAP2K6 p.Ile56Val Uncertain significance ★ ⚠ same type
MAP2K6 p.Leu186Val 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/map2k6-p-ser326phe (accessed [today's date]).

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