Is DPYSL2 p.Arg545His (c.1634G>A) pathogenic?

DPYSL2 p.Arg545His (c.1634G>A) is classified Uncertain significance in DPYSL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely benign (0.0856); Ultra-rare (popmax 0.0227%, afr).

How common is DPYSL2 p.Arg545His (c.1634G>A) in the general population?

DPYSL2 p.Arg545His (c.1634G>A) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about DPYSL2 p.Arg545His (c.1634G>A)?

AlphaMissense predicts likely benign (score 0.0856) — an in-silico prediction, not a clinical call.

DPYSL2 p.Arg545His

c.1634G>A · VCV3842367

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0856 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0856	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 141 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	24.9	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R440H vs ClinVar R545H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0227% African / African-American · 17/75,034 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.00149% 24/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,414
Admixed American	0.00167%	60,004
European (non-Finnish)	0.000508%	196,667

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: DPYSL2
Protein: p.Arg545His
Coding: c.1634G>A
MANE Select: NM_001197293
Type: single nucleotide variant
Location: chr8:26652294 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.49 · 15 PDB

Full DPYSL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DPYSL2 p.Arg545Cys Uncertain significance ★ ⚠ same residue
DRP2 p.Leu545Met Uncertain significance ★ ⚠ same residue
DRP2 p.Glu432Ter Pathogenic ★★ same type
DPYSL2 p.Asn492Ser Uncertain significance ★★ ⚠ same type
DPYSL2 p.Asp520Asn Uncertain significance ★★ ⚠ same type
DRP2 p.Ala205Val Uncertain significance ★★ ⚠ same type
DRP2 p.Ala643Thr Uncertain significance ★★ ⚠ same type
DRP2 p.Arg199His 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/dpysl2-p-arg545his (accessed [today's date]).

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