Is MAP3K8 p.Ser74= (c.222A>C) pathogenic?

MAP3K8 p.Ser74= (c.222A>C) is classified Benign/Likely benign in MAP3K8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Rare (popmax 0.125%, afr).

How common is MAP3K8 p.Ser74= (c.222A>C) in the general population?

MAP3K8 p.Ser74= (c.222A>C) is rare (popmax 0.125%, afr) (gnomAD).

MAP3K8 p.Ser74=

c.222A>C · rs55962705 · VCV1584423

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.125%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.7	GERP -3.2
Overall
CADD	0.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.125% African / African-American · 94/75,068 alleles

Filtering AF 0.105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0971%

Overall 0.0292% 471/1,614,232 alleles · rare exomes 367/1,461,874 · genomes 104/152,358 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.197%	508
African / African-Americangrpmax	0.125%	799
East Asian	0.107%	935
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Admixed American	0.035%	2,859
Middle Eastern	0.033%	3,031
European (non-Finnish)	0.0118%	8,489
South Asian	0.011%	9,109

Finnish 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: MAP3K8
Protein: p.Ser74=
Coding: c.222A>C
MANE Select: NM_005204
dbSNP: rs55962705
Type: single nucleotide variant
Location: chr10:30439160 (GRCh38)
Gene constraint: LOEUF 0.58 · pLI 0.73 (gnomAD)
Structure: AlphaFold pLDDT 74.13 · 3 PDB

Full MAP3K8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAP3K8 p.Ala35Ser Uncertain significance ★★ ⚠ same type
MAP3K8 p.Ala450Thr Uncertain significance ★★ same type
MAP3K8 p.Arg392Gly Uncertain significance ★★ ⚠ same type
MAP3K8 p.Arg408Ser Uncertain significance ★★ ⚠ same type
MAP3K8 p.Asn54Asp Uncertain significance ★★ ⚠ same type
MAP3K8 p.Gly67Asp Uncertain significance ★★ ⚠ same type
MAP3K8 p.Ile190Val Uncertain significance ★★ ⚠ same type
MAP3K8 p.Met277Ile 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/map3k8-p-ser74 (accessed [today's date]).

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