Is PACS1 p.Val751= (c.2253G>A) pathogenic?

PACS1 p.Val751= (c.2253G>A) is classified Likely benign in PACS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). Very rare (popmax 0.00529%, amr); Associated with Schuurs-Hoeijmakers syndrome.

What condition is associated with PACS1 p.Val751= (c.2253G>A)?

PACS1 p.Val751= (c.2253G>A) is associated with Schuurs-Hoeijmakers syndrome (ClinVar).

How common is PACS1 p.Val751= (c.2253G>A) in the general population?

PACS1 p.Val751= (c.2253G>A) is very rare (popmax 0.00529%, amr) (gnomAD).

PACS1 p.Val751=

c.2253G>A · rs558200737 · VCV2107682

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00529%, amr)

Conditions

Schuurs-Hoeijmakers syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.62, phastCons 1
Overall
CADD	14.54	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00529% Admixed American · 3/56,738 alleles

Filtering AF 0.0014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000689%

Overall 0.000378% 6/1,587,416 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00529%	18,913
Remaining individualsnot grpmax-eligible	0.00163%	61,420
European (non-Finnish)	0.000172%	582,428

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: PACS1
Protein: p.Val751=
Coding: c.2253G>A
MANE Select: NM_018026
dbSNP: rs558200737
Type: single nucleotide variant
Location: chr11:66238806 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 65.81 · 1 PDB

Full PACS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Schuurs-Hoeijmakers syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PACS1 p.Arg203Trp Pathogenic/Likely pathogenic ★★ same condition
PACS1 c.1038+3A>T Uncertain significance ★★ same condition
PACS1 c.1199+5G>A Uncertain significance ★★ same condition
PACS1 c.2776+4C>T Uncertain significance ★★ same condition
PACS1 p.Arg270Cys Uncertain significance ★★ ⚠ same condition
PACS1 p.Arg315Gln Uncertain significance ★★ ⚠ same condition
PACS1 p.Arg658Cys Uncertain significance ★★ same condition
PACS1 p.Asn813His 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/pacs1-p-val751 (accessed [today's date]).

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