Is PACS2 p.Pro391= (c.1173C>T) pathogenic?

PACS2 p.Pro391= (c.1173C>T) is classified Likely benign in PACS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0233%, amr).

How common is PACS2 p.Pro391= (c.1173C>T) in the general population?

PACS2 p.Pro391= (c.1173C>T) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

PACS2 p.Pro391=

c.1173C>T · rs200671786 · VCV1549040

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -15	GERP -3.2
Overall
CADD	0.515	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0233% Admixed American · 14/59,972 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00416% 67/1,612,376 alleles · ultra-rare exomes 59/1,460,058 · genomes 8/152,318 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0272%	3,672
Admixed Americangrpmax	0.0233%	4,284
African / African-American	0.0213%	4,692
Middle Eastern	0.0165%	6,056
European (non-Finnish)	0.00153%	65,533
South Asian	0.0011%	91,008

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: PACS2
Protein: p.Pro391=
Coding: c.1173C>T
MANE Select: NM_001100913
dbSNP: rs200671786
Type: single nucleotide variant
Location: chr14:105381004 (GRCh38)
Gene constraint: LOEUF 0.561 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.10
Residue 391: the 'disordered' region

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

Similar variants

PACS2 p.Glu209Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
PACS2 c.1413+2T>C Uncertain significance ★★ same type
PACS2 p.Ala526Val Uncertain significance ★★ ⚠ same type
PACS2 p.Ala704Thr Uncertain significance ★★ ⚠ same type
PACS2 p.Ala883Thr Uncertain significance ★★ ⚠ same type
PACS2 p.Arg431Gln Uncertain significance ★★ ⚠ same type
PACS2 p.Arg445Trp Uncertain significance ★★ ⚠ same type
PACS2 p.Arg514Lys Uncertain significance ★★ ⚠ 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/pacs2-p-pro391 (accessed [today's date]).

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