Is PACS2 p.Pro35Arg (c.104C>G) pathogenic?

PACS2 p.Pro35Arg (c.104C>G) is classified Uncertain significance in PACS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-18). AlphaMissense: likely pathogenic (0.6364); Very rare (popmax 0.00183%, sas).

How common is PACS2 p.Pro35Arg (c.104C>G) in the general population?

PACS2 p.Pro35Arg (c.104C>G) is very rare (popmax 0.00183%, sas) (gnomAD).

What do computational predictors say about PACS2 p.Pro35Arg (c.104C>G)?

AlphaMissense predicts likely pathogenic (score 0.6364) — an in-silico prediction, not a clinical call.

PACS2 p.Pro35Arg

c.104C>G · rs1431172087 · VCV2815133

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6364 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00183%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.6364	likely pathogenic
REVEL	0.163	moderately benign-leaning
SaProt	LLR -10.61	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 40 kb · p 0.67 · regional, not allelic
Overall
CADD	28.8	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 0.00183% South Asian · 1/54,734 alleles

Overall 8.16e-05% 1/1,225,998 alleles · very rare exomes 1/1,076,750 · genomes 0/149,248 · 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: PACS2
Protein: p.Pro35Arg
Coding: c.104C>G
MANE Select: NM_001100913
dbSNP: rs1431172087
Type: single nucleotide variant
Location: chr14:105315022 (GRCh38)

Full PACS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/pacs2-p-pro35arg (accessed [today's date]).

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