Is DUSP18 p.Arg99His (c.296G>A) pathogenic?

DUSP18 p.Arg99His (c.296G>A) is classified Uncertain significance in DUSP18 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-18). AlphaMissense: likely benign (0.1288); Very rare (popmax 0.00878%, sas).

How common is DUSP18 p.Arg99His (c.296G>A) in the general population?

DUSP18 p.Arg99His (c.296G>A) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about DUSP18 p.Arg99His (c.296G>A)?

AlphaMissense predicts likely benign (score 0.1288) — an in-silico prediction, not a clinical call.

DUSP18 p.Arg99His

c.296G>A · rs200346696 · VCV2357904

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1288	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -10.54	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.67, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 563 bp · p 0.42 · regional, not allelic
Overall
CADD	22.8	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 0.00878% South Asian · 8/91,088 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00743% 120/1,614,098 alleles · very rare exomes 109/1,461,888 · genomes 11/152,210 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.182%	548
Remaining individualsnot grpmax-eligible	0.016%	6,249
South Asiangrpmax	0.00878%	11,386
African / African-American	0.00667%	14,986
Admixed American	0.00667%	15,001
European (non-Finnish)	0.0033%	30,258

Ashkenazi Jewish 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: DUSP18
Protein: p.Arg99His
Coding: c.296G>A
MANE Select: NM_152511
dbSNP: rs200346696
Type: single nucleotide variant
Location: chr22:30663708 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 92.97 · 1 PDB
Residue 99: the tyrosine-protein phosphatase domain

Full DUSP18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DUSP18 p.Ala124Thr Uncertain significance ★ ⚠ same type
DUSP18 p.Ala130Val Uncertain significance ★ ⚠ same type
DUSP18 p.Ala7Ser Uncertain significance ★ ⚠ same type
DUSP18 p.Arg138Trp Uncertain significance ★ ⚠ same type
DUSP18 p.Arg13Gln Uncertain significance ★ ⚠ same type
DUSP18 p.Arg13Trp Uncertain significance ★ ⚠ same type
DUSP18 p.Arg142Gln Uncertain significance ★ ⚠ same type
DUSP18 p.Arg183Cys 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/dusp18-p-arg99his (accessed [today's date]).

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