Is POLR2A p.Leu725fs (c.2173dup) pathogenic?

POLR2A p.Leu725fs (c.2173dup) is classified Likely pathogenic in POLR2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-17). Associated with neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities.

POLR2A p.Leu725fs

Q: What condition is associated with POLR2A p.Leu725fs (c.2173dup)?

POLR2A p.Leu725fs (c.2173dup) is associated with neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (ClinVar).

c.2173dup · VCV3766788

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP -0.68, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: POLR2A
Protein: p.Leu725fs
Coding: c.2173dup
MANE Select: NM_000937
Type: Duplication
Location: chr17:7501552 (GRCh38)
Gene constraint: LOEUF 0.202 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.95 · 58 PDB
Residue 725: a UniProt-annotated variant site (in nedhib; mild)

Full POLR2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POLR2A p.Ala748fs Likely pathogenic ★ same condition
POLR2A p.Asp454fs Likely pathogenic ★ same condition
POLR2A p.Met467fs Likely pathogenic ★ same condition
POLR2A p.Ser8fs Likely pathogenic ★ same condition
POLR2A p.Tyr1720fs Likely pathogenic ★ same condition
POLR2A p.Arg1123Gln Pathogenic/Likely pathogenic ★★ same condition
POLR2A p.Arg1810Ter Pathogenic/Likely pathogenic ★★ same condition
POLR2A p.Arg460Gln Likely pathogenic ★★ 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/polr2a-p-leu725fs (accessed [today's date]).

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