Is CRYM p.Thr288= (c.864C>G) pathogenic?

CRYM p.Thr288= (c.864C>G) is classified Benign in CRYM (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 77.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant nonsyndromic hearing loss 40.

What condition is associated with CRYM p.Thr288= (c.864C>G)?

CRYM p.Thr288= (c.864C>G) is associated with autosomal dominant nonsyndromic hearing loss 40 (ClinVar).

CRYM p.Thr288=

Q: How common is CRYM p.Thr288= (c.864C>G) in the general population?

CRYM p.Thr288= (c.864C>G) is common (popmax 77.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.864C>G · rs14122 · VCV44241

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 77.7%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal dominant nonsyndromic hearing loss 40

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.8
Overall
CADD	0.018	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 77.7% African / African-American · 58,150/74,824 alleles

Filtering AF 77.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 77%

Overall 43.7% 703,703/1,611,502 alleles · common exomes 624,510/1,459,684 · genomes 79,193/151,818 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	77.7%	1
Finnishnot grpmax-eligible	47.7%	2
Ashkenazi Jewishnot grpmax-eligible	47.3%	2
Middle Eastern	47.1%	2
South Asian	45.9%	2
Remaining individualsnot grpmax-eligible	44.2%	2
Amishnot grpmax-eligible	41.9%	2
European (non-Finnish)	41.5%	2
Admixed American	40%	2
East Asian	35.2%	3

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.Thr288=
Coding: c.864C>G
MANE Select: NM_001376256
dbSNP: rs14122
Type: single nucleotide variant
Location: chr16:21261270 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.06 · 1 PDB
Residue 288: a β-strand

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

Disease context

autosomal dominant nonsyndromic hearing loss 40 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRYM p.Val4Leu Uncertain significance ★★ ⚠ same condition
CRYM c.325-12T>C Benign ★★ same condition
CRYM p.Tyr247= Benign ★★ same condition
CRYM p.Ala10Gly Uncertain significance ★ ⚠ same condition
CRYM p.Ala254Val Conflicting classifications of pathogenicity ★ ⚠ same condition
CRYM p.Ala303Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
CRYM p.Glu175Val Conflicting classifications of pathogenicity ★ ⚠ same condition
CRYM p.Gly84Asp Uncertain significance ★ ⚠ same condition

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-thr288 (accessed [today's date]).

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