Is MAP4K3 p.Ser496Arg (c.1488C>A) pathogenic?

MAP4K3 p.Ser496Arg (c.1488C>A) is classified Uncertain significance in MAP4K3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: likely benign (0.3229); Very rare (popmax 0.00213%, nfe).

How common is MAP4K3 p.Ser496Arg (c.1488C>A) in the general population?

MAP4K3 p.Ser496Arg (c.1488C>A) is very rare (popmax 0.00213%, nfe) (gnomAD).

What do computational predictors say about MAP4K3 p.Ser496Arg (c.1488C>A)?

AlphaMissense predicts likely benign (score 0.3229) — an in-silico prediction, not a clinical call.

MAP4K3 p.Ser496Arg

c.1488C>A · rs1421110475 · VCV2339633

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00213%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3229	likely benign
REVEL	0.008	strongly benign-leaning
SaProt	LLR -8.11	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 0.67	GERP -0.32, phastCons 0.059
Regional constraint	o/e 1.08	unconstrained · MANE · 76 kb · p 0.027 · regional, not allelic
Overall
CADD	17.1	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 0.00213% European (non-Finnish) · 25/1,172,360 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00124%

Overall 0.00186% 27/1,448,620 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00323%	31,001
European (non-Finnish)grpmax	0.00213%	46,894

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: MAP4K3
Protein: p.Ser496Arg
Coding: c.1488C>A
MANE Select: NM_003618
dbSNP: rs1421110475
Type: single nucleotide variant
Location: chr2:39286951 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.96 · 1 PDB
Residue 496: the 'disordered' region

Full MAP4K3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP4K3 p.Ala253Thr Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala310Val Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala391Glu Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala429Val Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala621Thr Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala664Pro Uncertain significance ★ ⚠ same type
MAP4K3 p.Ala75Thr Uncertain significance ★ ⚠ same type
MAP4K3 p.Arg482Lys 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/map4k3-p-ser496arg (accessed [today's date]).

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