Is MAP3K14 p.Pro316Ser (c.946C>T) pathogenic?

MAP3K14 p.Pro316Ser (c.946C>T) is classified Uncertain significance in MAP3K14 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-19). AlphaMissense: likely benign (0.0803); Very rare (popmax 0.000594%, nfe).

How common is MAP3K14 p.Pro316Ser (c.946C>T) in the general population?

MAP3K14 p.Pro316Ser (c.946C>T) is very rare (popmax 0.000594%, nfe) (gnomAD).

What do computational predictors say about MAP3K14 p.Pro316Ser (c.946C>T)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

MAP3K14 p.Pro316Ser

c.946C>T · VCV4935621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -8.23	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 3.9	GERP 0.34, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 396 bp · p 0.042 · regional, not allelic
Overall
CADD	18.83	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 0.000594% European (non-Finnish) · 7/1,178,612 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000435% 7/1,610,476 alleles · very rare exomes 5/1,458,290 · genomes 2/152,186 · joint denominator

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: MAP3K14
Protein: p.Pro316Ser
Coding: c.946C>T
MANE Select: NM_003954
Type: single nucleotide variant
Location: chr17:45286637 (GRCh38)
Gene constraint: LOEUF 0.263 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.00 · 8 PDB

Full MAP3K14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K14 p.Ala103Thr Uncertain significance ★★ ⚠ same type
MAP3K14 p.Ala142Ser Uncertain significance ★★ ⚠ same type
MAP3K14 p.Ala575Thr Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg131His Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg146Gln Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg218Gln Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg432Trp Uncertain significance ★★ ⚠ same type
MAP3K14 p.Arg99His 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/map3k14-p-pro316ser (accessed [today's date]).

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