Is SETD1A p.Pro1118Arg (c.3353C>G) pathogenic?

SETD1A p.Pro1118Arg (c.3353C>G) is classified Likely benign in SETD1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1287); Rare (popmax 0.138%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETD1A p.Pro1118Arg (c.3353C>G)?

SETD1A p.Pro1118Arg (c.3353C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1A p.Pro1118Arg (c.3353C>G) in the general population?

SETD1A p.Pro1118Arg (c.3353C>G) is rare (popmax 0.138%, nfe) (gnomAD).

What do computational predictors say about SETD1A p.Pro1118Arg (c.3353C>G)?

AlphaMissense predicts likely benign (score 0.1287) — an in-silico prediction, not a clinical call.

SETD1A p.Pro1118Arg

c.3353C>G · rs138754589 · VCV2352296

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1287 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.138%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1287	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -8.09	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 4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 14 kb · p 0.57 · regional, not allelic
Overall
CADD	19.7	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 0.138% European (non-Finnish) · 1,593/1,151,288 alleles

Filtering AF 0.133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.13%

Overall 0.113% 1,765/1,562,310 alleles · rare exomes 1,658/1,409,978 · genomes 107/152,332 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.165%	608
Ashkenazi Jewishnot grpmax-eligible	0.159%	630
European (non-Finnish)grpmax	0.138%	723
African / African-American	0.0231%	4,333
Admixed American	0.0224%	4,471
Middle Eastern	0.0174%	5,736
Finnishnot grpmax-eligible	0.00161%	62,076

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1118Arg
Coding: c.3353C>G
MANE Select: NM_014712
dbSNP: rs138754589
Type: single nucleotide variant
Location: chr16:30971714 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 1118: 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.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-pro1118arg (accessed [today's date]).

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