Is SETD5 p.Ser626Ter (c.1877C>G) pathogenic?

SETD5 p.Ser626Ter (c.1877C>G) is classified Likely pathogenic in SETD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-20). Absent from gnomAD v4.1; Associated with intellectual disability.

What condition is associated with SETD5 p.Ser626Ter (c.1877C>G)?

SETD5 p.Ser626Ter (c.1877C>G) is associated with intellectual disability (ClinVar).

How common is SETD5 p.Ser626Ter (c.1877C>G) in the general population?

SETD5 p.Ser626Ter (c.1877C>G) is absent from gnomAD v4.1 (gnomAD).

SETD5 p.Ser626Ter

c.1877C>G · rs2042188851 · VCV978945

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

intellectual disability

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 15 of 23
REVEL	0.37	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Overall
CADD	39.0	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

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: SETD5
Protein: p.Ser626Ter
Coding: c.1877C>G
MANE Select: NM_001080517
dbSNP: rs2042188851
Type: single nucleotide variant
Location: chr3:9447780 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 626: the 'disordered' region; a UniProt-annotated variant site (in mrd23)

Full SETD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD5 c.2347-1G>A Pathogenic ★★ same condition
SETD5 c.2347-7A>G Pathogenic ★★ same condition
SETD5 p.Ala182Ser Uncertain significance ★ ⚠ same condition
SETD5 p.Arg632Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
SETD5 p.Gln196Ter Conflicting classifications of pathogenicity ★ ⚠ same condition
SETD5 p.Gln216fs Pathogenic ★ same condition
SETD5 p.Leu723fs Pathogenic same condition
SETD5 p.Thr726fs 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/setd5-p-ser626ter (accessed [today's date]).

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