Is DPYSL5 p.Arg231His (c.692G>A) pathogenic?

DPYSL5 p.Arg231His (c.692G>A) is classified Uncertain significance in DPYSL5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: likely pathogenic (0.8672); Very rare (popmax 0.000424%, nfe); Associated with Ritscher-Schinzel syndrome 4.

What condition is associated with DPYSL5 p.Arg231His (c.692G>A)?

DPYSL5 p.Arg231His (c.692G>A) is associated with Ritscher-Schinzel syndrome 4 (ClinVar).

How common is DPYSL5 p.Arg231His (c.692G>A) in the general population?

DPYSL5 p.Arg231His (c.692G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about DPYSL5 p.Arg231His (c.692G>A)?

AlphaMissense predicts likely pathogenic (score 0.8672) — an in-silico prediction, not a clinical call.

DPYSL5 p.Arg231His

c.692G>A · VCV3257726

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ritscher-Schinzel syndrome 4

Computational evidence

Protein change
AlphaMissense	0.8672	likely pathogenic
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -12.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 44 kb · p 1e-21 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000424% European (non-Finnish) · 5/1,179,936 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,756 alleles · very rare

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: DPYSL5
Protein: p.Arg231His
Coding: c.692G>A
MANE Select: NM_020134
Type: single nucleotide variant
Location: chr2:26931662 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.21 · 3 PDB
Residue 231: an α-helix

Full DPYSL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ritscher-Schinzel syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DPYSL5 p.Arg231Cys Uncertain significance ★ ⚠ same residue
DPYSL5 p.Glu41Lys Pathogenic ★★ ⚠ same condition
DPYSL5 p.Val357Ile Uncertain significance ★★ ⚠ same condition
DPYSL5 c.-122G>T Uncertain significance ★ same condition
DPYSL5 p.Ala112Val Uncertain significance ★ ⚠ same condition
DPYSL5 p.Ala53Gly Uncertain significance ★ ⚠ same condition
DPYSL5 p.Arg551Gln Uncertain significance ★ ⚠ same condition
DPYSL5 p.Asn380Ser 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/dpysl5-p-arg231his (accessed [today's date]).

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