Is DPH5 p.Arg224Ser (c.672G>C) pathogenic?

DPH5 p.Arg224Ser (c.672G>C) is classified Uncertain significance in DPH5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.9726); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties.

How common is DPH5 p.Arg224Ser (c.672G>C) in the general population?

DPH5 p.Arg224Ser (c.672G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DPH5 p.Arg224Ser (c.672G>C)?

AlphaMissense predicts likely pathogenic (score 0.9726) — an in-silico prediction, not a clinical call.

DPH5 p.Arg224Ser

Q: What condition is associated with DPH5 p.Arg224Ser (c.672G>C)?

DPH5 p.Arg224Ser (c.672G>C) is associated with neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties (ClinVar).

c.672G>C · VCV4854881

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9726 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties

Computational evidence

Protein change
AlphaMissense	0.9726	likely pathogenic · top 10% in DPH5
REVEL	0.406	indeterminate
SaProt	LLR -12.85	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 0.015	GERP -4.5, phastCons 0.85
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.15 · regional, not allelic
Overall
CADD	21.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DPH5
Protein: p.Arg224Ser
Coding: c.672G>C
MANE Select: NM_015958
Type: single nucleotide variant
Location: chr1:100990594 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.20
Residue 224: a UniProt-annotated variant site (in nedsff; loss of function in diphthamide biosynthesis shown in a yeast assay system)

Full DPH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DPH5 p.His260Arg Pathogenic/Likely pathogenic ★★ same condition
DPH5 p.Pro104Thr Uncertain significance ★★ ⚠ same condition
DPH5 c.260+1G>T Likely pathogenic ★ same condition
DPH5 p.Ala223Val Uncertain significance ★ ⚠ same condition
DPH5 p.Leu163Pro Uncertain significance ★ ⚠ same condition
DPH5 p.Leu7Phe Uncertain significance ★ ⚠ same condition
DPH5 p.Leu94Val Uncertain significance ★ ⚠ same condition
DPH5 p.Pro184Leu 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/dph5-p-arg224ser (accessed [today's date]).

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