Is SETD1A p.Arg176Ter (c.526C>T) pathogenic?

SETD1A p.Arg176Ter (c.526C>T) is classified Pathogenic/Likely pathogenic in SETD1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-08-06). Very rare (popmax 0.00017%, nfe); Associated with neurodevelopmental disorder with speech impairment and dysmorphic facies.

What condition is associated with SETD1A p.Arg176Ter (c.526C>T)?

SETD1A p.Arg176Ter (c.526C>T) is associated with neurodevelopmental disorder with speech impairment and dysmorphic facies (ClinVar).

How common is SETD1A p.Arg176Ter (c.526C>T) in the general population?

SETD1A p.Arg176Ter (c.526C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

SETD1A p.Arg176Ter

c.526C>T · rs2543847896 · VCV1878499

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

neurodevelopmental disorder with speech impairment and dysmorphic facies

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 5 of 19
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,176,272 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,605,996 alleles · very rare exomes 2/1,453,678 · genomes 0/152,318 · joint denominator

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: SETD1A
Protein: p.Arg176Ter
Coding: c.526C>T
MANE Select: NM_014712
dbSNP: rs2543847896
Type: single nucleotide variant
Location: chr16:30963441 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 176: a UniProt-annotated variant site (in nedsid); an α-helix

Full SETD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with speech impairment and dysmorphic facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1A p.Arg668Ter Pathogenic ★★ same condition
SETD1A p.Arg1418His Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg276Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg311Pro Uncertain significance ★★ ⚠ same condition
SETD1A p.Lys1505Glu Uncertain significance ★★ ⚠ same condition
SETD1A p.Lys1567Asn Uncertain significance ★★ ⚠ same condition
SETD1A p.Pro392Thr 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/setd1a-p-arg176ter (accessed [today's date]).

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