Is PUM1 p.Pro20Ser (c.58C>T) pathogenic?

PUM1 p.Pro20Ser (c.58C>T) is classified Uncertain significance in PUM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-16). AlphaMissense: likely benign (0.2666); Very rare (popmax 0.00267%, afr).

How common is PUM1 p.Pro20Ser (c.58C>T) in the general population?

PUM1 p.Pro20Ser (c.58C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PUM1 p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.2666) — an in-silico prediction, not a clinical call.

PUM1 p.Pro20Ser

c.58C>T · rs1218121060 · VCV2579913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2666	likely benign
REVEL	0.377	indeterminate
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 95 kb · p 6.7e-19 · regional, not allelic
Overall
CADD	26.6	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 0.00267% African / African-American · 2/74,918 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,926 alleles · very rare exomes 0/1,461,768 · genomes 2/152,158 · 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: PUM1
Protein: p.Pro20Ser
Coding: c.58C>T
MANE Select: NM_001020658
dbSNP: rs1218121060
Type: single nucleotide variant
Location: chr1:31059509 (GRCh38)
Gene constraint: LOEUF 0.165 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.09 · 15 PDB

Full PUM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PUM1 p.Pro20Leu Uncertain significance ★ ⚠ same residue
PUM1 p.Pro20= Likely benign same residue
PUM1 p.Arg1010Ter Pathogenic/Likely pathogenic ★★ same type
PUM1 p.Arg1147Trp Pathogenic/Likely pathogenic ★★ same type
PUM1 c.364-4A>G Uncertain significance ★★ same type
PUM1 p.Ala433Thr Uncertain significance ★★ ⚠ same type
PUM1 p.Ala483Val Uncertain significance ★★ ⚠ same type
PUM1 p.Ala536Val 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/pum1-p-pro20ser (accessed [today's date]).

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