Is SETD1A p.Leu623Pro (c.1868T>C) pathogenic?

SETD1A p.Leu623Pro (c.1868T>C) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1491); Very rare (popmax 0.00119%, sas); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Leu623Pro (c.1868T>C)?

SETD1A p.Leu623Pro (c.1868T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Leu623Pro (c.1868T>C) in the general population?

SETD1A p.Leu623Pro (c.1868T>C) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about SETD1A p.Leu623Pro (c.1868T>C)?

AlphaMissense predicts likely benign (score 0.1491) — an in-silico prediction, not a clinical call.

SETD1A p.Leu623Pro

c.1868T>C · VCV4630560

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1491	likely benign
REVEL	0.289	benign-leaning
SaProt	LLR -4.82	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 2.9	GERP 2.3, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 981 bp · p 0.032 · regional, not allelic
Overall
CADD	22.7	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 0.00119% South Asian · 1/84,182 alleles

Overall 7.25e-05% 1/1,378,672 alleles · very rare exomes 1/1,245,318 · genomes 0/133,354 · 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.Leu623Pro
Coding: c.1868T>C
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30965749 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 623: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1A p.Ala671Thr Uncertain significance ★★ ⚠ same condition
SETD1A p.Ala840Val Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg1576Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg276Trp Uncertain significance ★★ ⚠ same condition
SETD1A p.Arg385His Uncertain significance ★★ ⚠ same condition
SETD1A p.Cys1638Phe Uncertain significance ★★ ⚠ same condition
SETD1A p.Glu1009Lys Uncertain significance ★★ ⚠ same condition
SETD1A p.Glu905Lys 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-leu623pro (accessed [today's date]).

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