Is PACS1 p.Leu685Pro (c.2054T>C) pathogenic?

PACS1 p.Leu685Pro (c.2054T>C) is classified Uncertain significance in PACS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.9339); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PACS1 p.Leu685Pro (c.2054T>C)?

PACS1 p.Leu685Pro (c.2054T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PACS1 p.Leu685Pro (c.2054T>C) in the general population?

PACS1 p.Leu685Pro (c.2054T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PACS1 p.Leu685Pro (c.2054T>C)?

AlphaMissense predicts likely pathogenic (score 0.9339) — an in-silico prediction, not a clinical call.

PACS1 p.Leu685Pro

c.2054T>C · VCV3927226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9339 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9339	likely pathogenic
REVEL	0.379	indeterminate
SaProt	LLR -13.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.66, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 20 kb · p 3e-11 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PACS1
Protein: p.Leu685Pro
Coding: c.2054T>C
MANE Select: NM_018026
Type: single nucleotide variant
Location: chr11:66234192 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PACS1 p.Asp691Asn Uncertain significance ★★ ⚠ same condition
PACS1 p.Gln36Glu Uncertain significance ★★ ⚠ same condition
PACS1 p.Leu664Phe Uncertain significance ★★ same condition
PACS1 p.Ser558Leu Uncertain significance ★★ same condition
PACS1 p.Ser57Phe Uncertain significance ★★ ⚠ same condition
PACS1 p.Ser845Leu Uncertain significance ★★ ⚠ same condition
PACS1 c.1293+6C>T Benign/Likely benign ★★ same condition
PACS1 c.2776+5G>A Benign/Likely benign ★★ 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-leu685pro (accessed [today's date]).

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