Is SETD5 p.Thr439Ser (c.1316C>G) pathogenic?

SETD5 p.Thr439Ser (c.1316C>G) is classified Uncertain significance in SETD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-08). AlphaMissense: likely pathogenic (0.9327); Very rare (popmax 0.000339%, nfe); Associated with Developmental disorder.

What condition is associated with SETD5 p.Thr439Ser (c.1316C>G)?

SETD5 p.Thr439Ser (c.1316C>G) is associated with Developmental disorder (ClinVar).

How common is SETD5 p.Thr439Ser (c.1316C>G) in the general population?

SETD5 p.Thr439Ser (c.1316C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about SETD5 p.Thr439Ser (c.1316C>G)?

AlphaMissense predicts likely pathogenic (score 0.9327) — an in-silico prediction, not a clinical call.

SETD5 p.Thr439Ser

c.1316C>G · rs770427830 · VCV2416368

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9327 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Developmental disorder

Computational evidence

Protein change
AlphaMissense	0.9327	likely pathogenic
REVEL	0.51	indeterminate
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 26 kb · p 0.85 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,874 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,976 alleles · very rare exomes 4/1,461,674 · genomes 0/152,302 · 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: SETD5
Protein: p.Thr439Ser
Coding: c.1316C>G
MANE Select: NM_001080517
dbSNP: rs770427830
Type: single nucleotide variant
Location: chr3:9445176 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 47.10
Residue 439: 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

Developmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD5 p.Thr439Ile Uncertain significance ★ ⚠ same residue
SETD5 p.Arg912Ter Pathogenic ★★ same condition
SETD5 p.Gln1058fs Pathogenic ★★ same condition
SETD5 c.1441-1G>A Pathogenic ★★ same type
SETD5 c.1525-1G>C Pathogenic/Likely pathogenic ★★ same type
SETD5 c.2347-1G>A Pathogenic ★★ same type
SETD5 c.2347-7A>G Pathogenic ★★ same type
SETD5 c.3631+1G>A Pathogenic ★★ same type

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-thr439ser (accessed [today's date]).

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