Is CREM p.Ser39Pro (c.115T>C) pathogenic?

CREM p.Ser39Pro (c.115T>C) is classified Uncertain significance in CREM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-02). AlphaMissense: likely benign (0.0707); Very rare (popmax 0.0011%, sas).

How common is CREM p.Ser39Pro (c.115T>C) in the general population?

CREM p.Ser39Pro (c.115T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CREM p.Ser39Pro (c.115T>C)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

CREM p.Ser39Pro

c.115T>C · VCV3269490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -5.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.94	GERP 0.83, phastCons 0.81
Regional constraint	o/e 0.92	unconstrained · MANE · 69 kb · p 0.17 · regional, not allelic
Overall
CADD	18.64	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S23P vs ClinVar S39P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,024 alleles

Overall 6.2e-05% 1/1,613,820 alleles · very rare exomes 1/1,461,550 · genomes 0/152,270 · 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: CREM
Protein: p.Ser39Pro
Coding: c.115T>C
MANE Select: NM_183011
Type: single nucleotide variant
Location: chr10:35148438 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 61.54

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

Similar variants

CREM p.Arg244= Benign ★★ same type
CREM p.Lys104= Benign ★★ same type
CREM p.Ser226Leu Likely benign ★★ same type
CREM c.*344A>G Uncertain significance ★ ⚠ same type
CREM c.*354A>G Uncertain significance ★ ⚠ same type
CREM c.*368C>A Uncertain significance ★ ⚠ same type
CREM p.Ala168Val Uncertain significance ★ ⚠ same type
CREM p.Ala58Ser 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/crem-p-ser39pro (accessed [today's date]).

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