Is MAP3K11 p.Pro685Ser (c.2053C>T) pathogenic?

MAP3K11 p.Pro685Ser (c.2053C>T) is classified Uncertain significance in MAP3K11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0681); Ultra-rare (popmax 0.0143%, nfe).

How common is MAP3K11 p.Pro685Ser (c.2053C>T) in the general population?

MAP3K11 p.Pro685Ser (c.2053C>T) is ultra-rare (popmax 0.0143%, nfe) (gnomAD).

What do computational predictors say about MAP3K11 p.Pro685Ser (c.2053C>T)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

MAP3K11 p.Pro685Ser

c.2053C>T · rs201108277 · VCV3122843

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -7.76	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 0.3	GERP -1.2
Regional constraint	o/e 1.03	unconstrained · MANE · 9,072 bp · p 0.49 · regional, not allelic
Overall
CADD	4.701	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 0.0143% European (non-Finnish) · 161/1,129,088 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0115% 171/1,493,138 alleles · ultra-rare exomes 143/1,340,972 · genomes 28/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0143%	7,013
Remaining individualsnot grpmax-eligible	0.0105%	9,500
Finnishnot grpmax-eligible	0.00332%	30,152
African / African-American	0.00296%	33,823

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: MAP3K11
Protein: p.Pro685Ser
Coding: c.2053C>T
MANE Select: NM_002419
dbSNP: rs201108277
Type: single nucleotide variant
Location: chr11:65599547 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.79 · 4 PDB
Residue 685: the 'disordered' region

Full MAP3K11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K11 p.Ala169Thr Uncertain significance ★ ⚠ same type
MAP3K11 p.Ala282Pro Uncertain significance ★ ⚠ same type
MAP3K11 p.Ala287Thr Uncertain significance ★ ⚠ same type
MAP3K11 p.Ala352Ser Uncertain significance ★ ⚠ same type
MAP3K11 p.Ala370Val Uncertain significance ★ ⚠ same type
MAP3K11 p.Ala378Thr Uncertain significance ★ ⚠ same type
MAP3K11 p.Ala39Gly Uncertain significance ★ ⚠ same type
MAP3K11 p.Ala42Ser 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/map3k11-p-pro685ser (accessed [today's date]).

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