Is CREM p.Ala58Ser (c.172G>T) pathogenic?

CREM p.Ala58Ser (c.172G>T) is classified Uncertain significance in CREM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0884); Ultra-rare (popmax 0.0458%, sas).

How common is CREM p.Ala58Ser (c.172G>T) in the general population?

CREM p.Ala58Ser (c.172G>T) is ultra-rare (popmax 0.0458%, sas) (gnomAD).

What do computational predictors say about CREM p.Ala58Ser (c.172G>T)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

CREM p.Ala58Ser

c.172G>T · VCV4234102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0458%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -6.37	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 8.6	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 69 kb · p 0.17 · regional, not allelic
Overall
CADD	20.1	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 A91S vs ClinVar A58S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0458% South Asian · 41/89,538 alleles

Filtering AF 0.0346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0307%

Overall 0.00268% 43/1,606,186 alleles · ultra-rare exomes 42/1,454,034 · genomes 1/152,152 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0458%	2,184
Remaining individualsnot grpmax-eligible	0.00322%	31,100

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.Ala58Ser
Coding: c.172G>T
MANE Select: NM_183011
Type: single nucleotide variant
Location: chr10:35178892 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 61.54
Residue 91 UniProt numbering: the kid domain

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.Arg211Gln 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-ala58ser (accessed [today's date]).

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