Is CRYM p.Thr48Pro (c.142A>C) pathogenic?

CRYM p.Thr48Pro (c.142A>C) is classified Uncertain significance in CRYM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). AlphaMissense: likely pathogenic (0.6214); Ultra-rare (popmax 0.0293%, eas).

How common is CRYM p.Thr48Pro (c.142A>C) in the general population?

CRYM p.Thr48Pro (c.142A>C) is ultra-rare (popmax 0.0293%, eas) (gnomAD).

What do computational predictors say about CRYM p.Thr48Pro (c.142A>C)?

AlphaMissense predicts likely pathogenic (score 0.6214) — an in-silico prediction, not a clinical call.

CRYM p.Thr48Pro

c.142A>C · VCV3603856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6214 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6214	likely pathogenic
REVEL	0.733	pathogenic-leaning
SaProt	LLR -9.63	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 19 kb · p 0.0044 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0293% East Asian · 12/40,886 alleles

Filtering AF 0.0169% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.000775% 12/1,547,924 alleles · ultra-rare exomes 10/1,395,802 · genomes 2/152,122 · 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: CRYM
Protein: p.Thr48Pro
Coding: c.142A>C
MANE Select: NM_001376256
Type: single nucleotide variant
Location: chr16:21278110 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.06 · 1 PDB
Residue 48: a β-strand

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

Similar variants

CRYM p.Thr48= Likely benign ★★ same residue
CRYM p.Ala178Glu Uncertain significance ★★ ⚠ same type
CRYM p.Glu172Gly Uncertain significance ★★ ⚠ same type
CRYM p.Leu72Val Uncertain significance ★★ ⚠ same type
CRYM p.Met295Ile Uncertain significance ★★ ⚠ same type
CRYM p.Thr95Ser Uncertain significance ★★ ⚠ same type
CRYM p.Val4Leu Uncertain significance ★★ ⚠ same type
CRYM c.171-118C>T Benign ★★ 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/crym-p-thr48pro (accessed [today's date]).

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