Is MAP2K4 p.Ser5Ile (c.14G>T) pathogenic?

MAP2K4 p.Ser5Ile (c.14G>T) is classified Uncertain significance in MAP2K4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.2267); Very rare (popmax 0.00625%, nfe).

How common is MAP2K4 p.Ser5Ile (c.14G>T) in the general population?

MAP2K4 p.Ser5Ile (c.14G>T) is very rare (popmax 0.00625%, nfe) (gnomAD).

What do computational predictors say about MAP2K4 p.Ser5Ile (c.14G>T)?

AlphaMissense predicts likely benign (score 0.2267) — an in-silico prediction, not a clinical call.

MAP2K4 p.Ser5Ile

c.14G>T · rs1161471824 · VCV2237579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2267 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00625%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2267	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -8.94	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 7.4	GERP 0.14, phastCons 1
Regional constraint	o/e 1.23	unconstrained · MANE · 114 bp · p 0.087 · regional, not allelic
Overall
CADD	23.7	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 0.00625% European (non-Finnish) · 61/976,064 alleles

Filtering AF 0.00496% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00449%

Overall 0.00536% 65/1,213,508 alleles · very rare exomes 52/1,061,640 · genomes 13/151,868 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00625%	16,001
Remaining individualsnot grpmax-eligible	0.00451%	22,157
Finnishnot grpmax-eligible	0.00321%	31,114
African / African-American	0.00157%	63,582

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: MAP2K4
Protein: p.Ser5Ile
Coding: c.14G>T
MANE Select: NM_003010
dbSNP: rs1161471824
Type: single nucleotide variant
Location: chr17:12020900 (GRCh38)
Gene constraint: LOEUF 0.216 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.39 · 4 PDB
Residue 5: the 'disordered' region

Full MAP2K4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP2K4 c.116-2A>C Uncertain significance ★ same type
MAP2K4 p.Ala33Val Uncertain significance ★ ⚠ same type
MAP2K4 p.Ala378Pro Uncertain significance ★ same type
MAP2K4 p.Arg262Gly Uncertain significance ★ ⚠ same type
MAP2K4 p.Arg58Gly Uncertain significance ★ same type
MAP2K4 p.Asn242Ser Uncertain significance ★ ⚠ same type
MAP2K4 p.Asp157Glu Uncertain significance ★ ⚠ same type
MAP2K4 p.Gln316Leu 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/map2k4-p-ser5ile (accessed [today's date]).

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