Is DUSP18 p.Ser74Phe (c.221C>T) pathogenic?

DUSP18 p.Ser74Phe (c.221C>T) is classified Uncertain significance in DUSP18 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely benign (0.305); Ultra-rare (popmax 0.0226%, nfe).

How common is DUSP18 p.Ser74Phe (c.221C>T) in the general population?

DUSP18 p.Ser74Phe (c.221C>T) is ultra-rare (popmax 0.0226%, nfe) (gnomAD).

What do computational predictors say about DUSP18 p.Ser74Phe (c.221C>T)?

AlphaMissense predicts likely benign (score 0.305) — an in-silico prediction, not a clinical call.

DUSP18 p.Ser74Phe

c.221C>T · rs200899592 · VCV2458664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.305 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.305	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -9.28	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 2.5	GERP -1.5, phastCons 0.072
Regional constraint	o/e 0.95	unconstrained · MANE · 563 bp · p 0.42 · regional, not allelic
Overall
CADD	8.314	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 0.0226% European (non-Finnish) · 267/1,180,032 alleles

Filtering AF 0.0204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.0177% 286/1,614,198 alleles · ultra-rare exomes 259/1,461,890 · genomes 27/152,308 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0226%	4,420
Admixed American	0.02%	5,001
Remaining individualsnot grpmax-eligible	0.0096%	10,419
African / African-American	0.00133%	75,066

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.Ser74Phe
Coding: c.221C>T
MANE Select: NM_152511
dbSNP: rs200899592
Type: single nucleotide variant
Location: chr22:30663783 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 92.97 · 1 PDB
Residue 74: 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-ser74phe (accessed [today's date]).

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