Is SETD1B p.Pro701Ala (c.2101C>G) pathogenic?

SETD1B p.Pro701Ala (c.2101C>G) is classified Likely benign in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-24). AlphaMissense: likely benign (0.0717); Ultra-rare (popmax 0.0691%, sas).

How common is SETD1B p.Pro701Ala (c.2101C>G) in the general population?

SETD1B p.Pro701Ala (c.2101C>G) is ultra-rare (popmax 0.0691%, sas) (gnomAD).

What do computational predictors say about SETD1B p.Pro701Ala (c.2101C>G)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

SETD1B p.Pro701Ala

c.2101C>G · VCV4918952

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0691%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -7.76	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 2.9	GERP 1.6, phastCons 0.98
Regional constraint	o/e 0.97	unconstrained · MANE · 3,957 bp · p 0.61 · regional, not allelic
Overall
CADD	11.21	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 0.0691% South Asian · 46/66,604 alleles

Filtering AF 0.0532% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0475%

Overall 0.00445% 52/1,169,410 alleles · ultra-rare exomes 50/1,047,318 · genomes 2/122,092 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0691%	1,448
Remaining individualsnot grpmax-eligible	0.00422%	23,708
European (non-Finnish)	0.000467%	214,316

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: SETD1B
Protein: p.Pro701Ala
Coding: c.2101C>G
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121814316 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 701: the 'disordered' region

Full SETD1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SETD1B p.Arg1329Ter Pathogenic ★★ same type
SETD1B p.Arg1703Ter Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1748Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Arg1792Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
SETD1B p.Arg1825Trp Likely pathogenic ★★ same type
SETD1B p.Arg1902Cys Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Gln780Ter Pathogenic/Likely pathogenic ★★ same type
SETD1B p.Glu1948Lys Pathogenic/Likely 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/setd1b-p-pro701ala (accessed [today's date]).

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