Is PACS2 p.Val164Phe (c.490G>T) pathogenic?

PACS2 p.Val164Phe (c.490G>T) is classified Benign in PACS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: likely benign (0.0978); Very rare (popmax 0.00266%, afr).

How common is PACS2 p.Val164Phe (c.490G>T) in the general population?

PACS2 p.Val164Phe (c.490G>T) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about PACS2 p.Val164Phe (c.490G>T)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

PACS2 p.Val164Phe

c.490G>T · rs1555408179 · VCV2417279

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -9.00	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 2.8	GERP 0.59, phastCons 0.17
Regional constraint	o/e 0.81	unconstrained · MANE · 27 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	21.2	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 0.00266% African / African-American · 2/75,058 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,172 alleles · very rare exomes 3/1,460,834 · genomes 0/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00266%	37,529
South Asian	0.0011%	91,084

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.Val164Phe
Coding: c.490G>T
MANE Select: NM_001100913
dbSNP: rs1555408179
Type: single nucleotide variant
Location: chr14:105367279 (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.Val164Ile Uncertain significance ★ ⚠ 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-val164phe (accessed [today's date]).

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