Is DPH5 p.Leu7Phe (c.21G>C) pathogenic?

DPH5 p.Leu7Phe (c.21G>C) is classified Uncertain significance in DPH5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely pathogenic (0.837); Very rare (popmax 0.00891%, eas); Associated with neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties.

How common is DPH5 p.Leu7Phe (c.21G>C) in the general population?

DPH5 p.Leu7Phe (c.21G>C) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about DPH5 p.Leu7Phe (c.21G>C)?

AlphaMissense predicts likely pathogenic (score 0.837) — an in-silico prediction, not a clinical call.

DPH5 p.Leu7Phe

Q: What condition is associated with DPH5 p.Leu7Phe (c.21G>C)?

DPH5 p.Leu7Phe (c.21G>C) is associated with neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties (ClinVar).

c.21G>C · VCV4854160

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.837 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.837	likely pathogenic
REVEL	0.683	pathogenic-leaning
SaProt	LLR -13.64	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 4.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.15 · regional, not allelic
Overall
CADD	25.4	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 0.00891% East Asian · 4/44,880 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000274% 4/1,461,868 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: DPH5
Protein: p.Leu7Phe
Coding: c.21G>C
MANE Select: NM_015958
Type: single nucleotide variant
Location: chr1:101025423 (GRCh38)
Gene constraint: LOEUF 1.295 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.20

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.Arg224Ser Uncertain significance ★ ⚠ same condition
DPH5 p.Leu163Pro 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-leu7phe (accessed [today's date]).

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