Is CREM p.Asn93Ser (c.278A>G) pathogenic?

CREM p.Asn93Ser (c.278A>G) is classified Uncertain significance in CREM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely benign (0.1319); Very rare (popmax 0.000679%, nfe).

How common is CREM p.Asn93Ser (c.278A>G) in the general population?

CREM p.Asn93Ser (c.278A>G) is very rare (popmax 0.000679%, nfe) (gnomAD).

What do computational predictors say about CREM p.Asn93Ser (c.278A>G)?

AlphaMissense predicts likely benign (score 0.1319) — an in-silico prediction, not a clinical call.

CREM p.Asn93Ser

c.278A>G · rs761583527 · VCV2219806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1319 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000679%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1319	likely benign
REVEL	0.624	indeterminate
SaProt	LLR -10.15	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 69 kb · p 0.17 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM N126S vs ClinVar N93S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000679% European (non-Finnish) · 8/1,178,848 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000559% 9/1,611,198 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,354
European (non-Finnish)grpmax	0.000679%	147,356

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asn93Ser
Coding: c.278A>G
MANE Select: NM_183011
dbSNP: rs761583527
Type: single nucleotide variant
Location: chr10:35179145 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 61.54
Residue 93: 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.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-asn93ser (accessed [today's date]).

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