Is SETD1A p.Arg1205Pro (c.3614G>C) pathogenic?

SETD1A p.Arg1205Pro (c.3614G>C) is classified Uncertain significance in SETD1A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-30). AlphaMissense: ambiguous (0.4851); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Arg1205Pro (c.3614G>C)?

SETD1A p.Arg1205Pro (c.3614G>C) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Arg1205Pro (c.3614G>C) in the general population?

SETD1A p.Arg1205Pro (c.3614G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SETD1A p.Arg1205Pro (c.3614G>C)?

AlphaMissense predicts ambiguous (score 0.4851) — an in-silico prediction, not a clinical call.

SETD1A p.Arg1205Pro

c.3614G>C · VCV3440158

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4851	ambiguous
REVEL	0.491	indeterminate
SaProt	LLR -6.70	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.57 · regional, not allelic
Overall
CADD	25.3	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 8.48e-05% European (non-Finnish) · 1/1,179,156 alleles

Overall 6.21e-05% 1/1,611,400 alleles · very rare exomes 1/1,459,098 · 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: SETD1A
Protein: p.Arg1205Pro
Coding: c.3614G>C
MANE Select: NM_014712
Type: single nucleotide variant
Location: chr16:30979400 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 1205: the 'disordered' region; a UniProt-annotated variant site (in nedsid)

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.Arg1205Gly Uncertain significance ★ ⚠ same residue
SETD1A p.Arg1205Gln Likely benign ★ same residue
SETD1A p.Arg1205Trp Uncertain significance ★ same residue
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

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-arg1205pro (accessed [today's date]).

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