Is PUM2 p.Phe683Ser (c.2048T>C) pathogenic?

PUM2 p.Phe683Ser (c.2048T>C) is classified Uncertain significance in PUM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). Very rare (popmax 8.47e-05%, nfe).

How common is PUM2 p.Phe683Ser (c.2048T>C) in the general population?

PUM2 p.Phe683Ser (c.2048T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

PUM2 p.Phe683Ser

c.2048T>C · VCV4148324

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.327	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 61 kb · p 1.8e-08 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 6.2e-05% 1/1,614,202 alleles · very rare exomes 1/1,461,846 · genomes 0/152,356 · 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: PUM2
Protein: p.Phe683Ser
Coding: c.2048T>C
MANE Select: NM_015317
Type: single nucleotide variant
Location: chr2:20263370 (GRCh38)
Gene constraint: LOEUF 0.576 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.75 · 3 PDB

Full PUM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PUM2 c.349-2A>G Uncertain significance ★ same type
PUM2 p.Ala1040Val Uncertain significance ★ same type
PUM2 p.Ala167Val Uncertain significance ★ same type
PUM2 p.Ala181Ser Uncertain significance ★ same type
PUM2 p.Ala251Thr Uncertain significance ★ same type
PUM2 p.Ala317Gly Uncertain significance ★ same type
PUM2 p.Ala326Val Uncertain significance ★ same type
PUM2 p.Ala365Val 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/pum2-p-phe683ser (accessed [today's date]).

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