Is SETD1A p.Pro650Leu (c.1949C>T) pathogenic?

SETD1A p.Pro650Leu (c.1949C>T) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-22). AlphaMissense: likely benign (0.1445); Very rare (popmax 0.00447%, eas); Associated with epilepsy, early-onset, with or without developmental delay.

What condition is associated with SETD1A p.Pro650Leu (c.1949C>T)?

SETD1A p.Pro650Leu (c.1949C>T) is associated with epilepsy, early-onset, with or without developmental delay, neurodevelopmental disorder with speech impairment and dysmorphic facies (ClinVar).

How common is SETD1A p.Pro650Leu (c.1949C>T) in the general population?

SETD1A p.Pro650Leu (c.1949C>T) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about SETD1A p.Pro650Leu (c.1949C>T)?

AlphaMissense predicts likely benign (score 0.1445) — an in-silico prediction, not a clinical call.

SETD1A p.Pro650Leu

c.1949C>T · rs1051816095 · VCV983324

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1445 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

epilepsy, early-onset, with or without developmental delay

Computational evidence

Protein change
AlphaMissense	0.1445	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -8.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 981 bp · p 0.032 · regional, not allelic
Overall
CADD	22.4	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

Grpmax group 0.00447% East Asian · 2/44,752 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000312% 5/1,604,880 alleles · very rare exomes 3/1,453,242 · genomes 2/151,638 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,376
African / African-American	0.00134%	74,596
South Asian	0.00111%	90,044
European (non-Finnish)	8.51e-05%	1,174,633

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.Pro650Leu
Coding: c.1949C>T
MANE Select: NM_014712
dbSNP: rs1051816095
Type: single nucleotide variant
Location: chr16:30965830 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 650: 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

epilepsy, early-onset, with or without developmental delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodevelopmental disorder with speech impairment and dysmorphic facies

Similar variants

SETD1A p.Pro650Arg Uncertain significance ★ same residue
SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1A p.Arg176Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1A p.Arg668Ter Pathogenic ★★ same condition
SETD1A p.Arg913Cys Likely pathogenic ★★ ⚠ same condition
SETD1A p.Arg990Ter Pathogenic/Likely pathogenic ★★ same condition
SETD1A p.Arg1392His Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg1418His 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-pro650leu (accessed [today's date]).

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