Is PACS2 p.Pro280Ser (c.838C>T) pathogenic?

PACS2 p.Pro280Ser (c.838C>T) is classified Uncertain significance in PACS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-02). AlphaMissense: likely benign (0.1001); Very rare (popmax 0.00333%, amr).

How common is PACS2 p.Pro280Ser (c.838C>T) in the general population?

PACS2 p.Pro280Ser (c.838C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about PACS2 p.Pro280Ser (c.838C>T)?

AlphaMissense predicts likely benign (score 0.1001) — an in-silico prediction, not a clinical call.

PACS2 p.Pro280Ser

c.838C>T · rs2080797624 · VCV1356903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1001 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1001	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -6.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 0.79, phastCons 0.93
Regional constraint	o/e 0.81	unconstrained · MANE · 27 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00333% Admixed American · 2/59,998 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,164 alleles · very rare exomes 2/1,460,878 · genomes 0/152,286 · 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.Pro280Ser
Coding: c.838C>T
MANE Select: NM_001100913
dbSNP: rs2080797624
Type: single nucleotide variant
Location: chr14:105376804 (GRCh38)
Gene constraint: LOEUF 0.561 · pLI 0.33 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.10

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

Similar variants

PACS2 p.Pro280= Benign ★ same residue
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

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-pro280ser (accessed [today's date]).

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