Is DPYS p.Ile185Ser (c.554T>G) pathogenic?

DPYS p.Ile185Ser (c.554T>G) is classified Uncertain significance in DPYS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-18). AlphaMissense: likely benign (0.2574); Ultra-rare (popmax 0.0351%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DPYS p.Ile185Ser (c.554T>G)?

DPYS p.Ile185Ser (c.554T>G) is associated with Inborn genetic diseases (ClinVar).

How common is DPYS p.Ile185Ser (c.554T>G) in the general population?

DPYS p.Ile185Ser (c.554T>G) is ultra-rare (popmax 0.0351%, nfe) (gnomAD).

What do computational predictors say about DPYS p.Ile185Ser (c.554T>G)?

AlphaMissense predicts likely benign (score 0.2574) — an in-silico prediction, not a clinical call.

DPYS p.Ile185Ser

c.554T>G · rs147772269 · VCV1421032

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2574 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2574	likely benign
REVEL	0.66	pathogenic-leaning
SaProt	LLR -10.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 0.73, phastCons 0.97
Regional constraint	o/e 0.97	unconstrained · MANE · 86 kb · p 0.4 · regional, not allelic
Overall
CADD	23.9	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 0.0351% European (non-Finnish) · 414/1,179,996 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.027% 436/1,613,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0351%	2,850
Remaining individualsnot grpmax-eligible	0.0176%	5,680
Finnishnot grpmax-eligible	0.00625%	16,009
African / African-American	0.00534%	18,724
Admixed American	0.00334%	29,984
South Asian	0.0011%	91,066

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: DPYS
Protein: p.Ile185Ser
Coding: c.554T>G
MANE Select: NM_001385
dbSNP: rs147772269
Type: single nucleotide variant
Location: chr8:104447373 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 1 PDB
Residue 185: an α-helix

Full DPYS 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

DPYS p.Ser379Arg Pathogenic/Likely pathogenic ★★ same condition
DPYS p.Ala47Gly Uncertain significance ★★ ⚠ same condition
DPYS p.Ala491Val Uncertain significance ★★ ⚠ same condition
DPYS p.Asn347Ser Uncertain significance ★★ ⚠ same condition
DPYS p.Asp140Asn Uncertain significance ★★ ⚠ same condition
DPYS p.Asp309Tyr Uncertain significance ★★ ⚠ same condition
DPYS p.Glu115Lys Uncertain significance ★★ ⚠ same condition
DPYS p.Gly216Asp 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/dpys-p-ile185ser (accessed [today's date]).

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