Is CREM p.Tyr88Phe (c.263A>T) pathogenic?

CREM p.Tyr88Phe (c.263A>T) is classified Uncertain significance in CREM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: ambiguous (0.426); Very rare (popmax 0.00102%, nfe).

How common is CREM p.Tyr88Phe (c.263A>T) in the general population?

CREM p.Tyr88Phe (c.263A>T) is very rare (popmax 0.00102%, nfe) (gnomAD).

What do computational predictors say about CREM p.Tyr88Phe (c.263A>T)?

AlphaMissense predicts ambiguous (score 0.426) — an in-silico prediction, not a clinical call.

CREM p.Tyr88Phe

c.263A>T · rs757430447 · VCV2215389

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.426 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.426	ambiguous
REVEL	0.847	moderately pathogenic-leaning
SaProt	LLR -12.23	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 69 kb · p 0.17 · regional, not allelic
Overall
CADD	27.1	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 Y121F vs ClinVar Y88F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,175,548 alleles

Filtering AF 0.000544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00043%

Overall 0.000812% 13/1,601,188 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	61,940
European (non-Finnish)grpmax	0.00102%	97,962

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.Tyr88Phe
Coding: c.263A>T
MANE Select: NM_183011
dbSNP: rs757430447
Type: single nucleotide variant
Location: chr10:35178983 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 61.54
Residue 88: 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-tyr88phe (accessed [today's date]).

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