Is SETD1A p.Arg72Ile (c.215G>T) pathogenic?

SETD1A p.Arg72Ile (c.215G>T) is classified Uncertain significance in SETD1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-10). AlphaMissense: likely pathogenic (0.8115); Very rare (popmax 0.000254%, nfe).

How common is SETD1A p.Arg72Ile (c.215G>T) in the general population?

SETD1A p.Arg72Ile (c.215G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about SETD1A p.Arg72Ile (c.215G>T)?

AlphaMissense predicts likely pathogenic (score 0.8115) — an in-silico prediction, not a clinical call.

SETD1A p.Arg72Ile

c.215G>T · rs774708325 · VCV1521607

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8115	likely pathogenic
REVEL	0.24	benign-leaning
SaProt	LLR -5.60	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 432 bp · p 0.038 · regional, not allelic
Overall
CADD	28.7	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 0.000254% European (non-Finnish) · 3/1,179,514 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,610 alleles · very rare exomes 3/1,461,334 · genomes 0/152,276 · 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.Arg72Ile
Coding: c.215G>T
MANE Select: NM_014712
dbSNP: rs774708325
Type: single nucleotide variant
Location: chr16:30959155 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 72: the 'interaction with wdr82' region; a UniProt-annotated variant site (in nedsid)

Full SETD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD1A p.Arg72fs Pathogenic ★ same residue
SETD1A c.518-2A>G Pathogenic ★★ same type
SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg176Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg668Ter Pathogenic ★★ same type
SETD1A p.Arg913Cys Likely pathogenic ★★ ⚠ same type
SETD1A p.Arg990Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Tyr646Ter 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/setd1a-p-arg72ile (accessed [today's date]).

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