Is SETD1A p.Pro600Thr (c.1798C>A) pathogenic?

SETD1A p.Pro600Thr (c.1798C>A) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely benign (0.0729); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder with speech impairment and dysmorphic facies.

What condition is associated with SETD1A p.Pro600Thr (c.1798C>A)?

SETD1A p.Pro600Thr (c.1798C>A) is associated with neurodevelopmental disorder with speech impairment and dysmorphic facies (ClinVar).

How common is SETD1A p.Pro600Thr (c.1798C>A) in the general population?

SETD1A p.Pro600Thr (c.1798C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SETD1A p.Pro600Thr (c.1798C>A)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

SETD1A p.Pro600Thr

c.1798C>A · VCV4531605

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with speech impairment and dysmorphic facies

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -9.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 2.2, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 981 bp · p 0.032 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

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: SETD1A
Protein: p.Pro600Thr
Coding: c.1798C>A
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30965679 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 600: a UniProt-annotated variant site (in nedsid); the 'disordered' region

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.Arg176Ter 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

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-pro600thr (accessed [today's date]).

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