Is MAP3K1 p.Ser778Arg (c.2332A>C) pathogenic?

MAP3K1 p.Ser778Arg (c.2332A>C) is classified Uncertain significance in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). AlphaMissense: ambiguous (0.4992); Very rare (popmax 0.00669%, eas); Associated with Inborn genetic diseases.

What condition is associated with MAP3K1 p.Ser778Arg (c.2332A>C)?

MAP3K1 p.Ser778Arg (c.2332A>C) is associated with Inborn genetic diseases (ClinVar).

How common is MAP3K1 p.Ser778Arg (c.2332A>C) in the general population?

MAP3K1 p.Ser778Arg (c.2332A>C) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about MAP3K1 p.Ser778Arg (c.2332A>C)?

AlphaMissense predicts ambiguous (score 0.4992) — an in-silico prediction, not a clinical call.

MAP3K1 p.Ser778Arg

c.2332A>C · rs775415674 · VCV3122798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4992	ambiguous
REVEL	0.255	benign-leaning
SaProt	LLR -7.29	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 0.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.13 · regional, not allelic
Overall
CADD	21.2	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 0.00669% East Asian · 3/44,854 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000186% 3/1,613,622 alleles · very rare exomes 2/1,461,442 · genomes 1/152,180 · 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: MAP3K1
Protein: p.Ser778Arg
Coding: c.2332A>C
MANE Select: NM_005921
dbSNP: rs775415674
Type: single nucleotide variant
Location: chr5:56881235 (GRCh38)
Gene constraint: LOEUF 0.355 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.80 · 1 PDB

Full MAP3K1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAP3K1 p.Ala594Ser Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Arg204Lys Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Val1346Ile Uncertain significance ★★ ⚠ same condition
MAP3K1 p.Pro962= Benign/Likely benign ★★ same condition
MAP3K1 p.Leu189Gln Likely pathogenic ★ ⚠ same condition
MAP3K1 p.Ala1017Val Uncertain significance ★ ⚠ same condition
MAP3K1 p.Ala1327Pro Uncertain significance ★ ⚠ same condition
MAP3K1 p.Ala1402Gly Uncertain significance ★ ⚠ same condition

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/map3k1-p-ser778arg (accessed [today's date]).

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