Is CRYGD p.Pro24Thr (c.70C>A) pathogenic?

CRYGD p.Pro24Thr (c.70C>A) is classified Pathogenic/Likely pathogenic in CRYGD (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-04). AlphaMissense: likely benign (0.1113); Very rare (popmax 0.0011%, sas); Associated with CRYGD-related disorders.

What condition is associated with CRYGD p.Pro24Thr (c.70C>A)?

CRYGD p.Pro24Thr (c.70C>A) is associated with CRYGD-related disorders, cataract 4 multiple types (ClinVar).

How common is CRYGD p.Pro24Thr (c.70C>A) in the general population?

CRYGD p.Pro24Thr (c.70C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CRYGD p.Pro24Thr (c.70C>A)?

AlphaMissense predicts likely benign (score 0.1113) — an in-silico prediction, not a clinical call.

CRYGD p.Pro24Thr

c.70C>A · rs28931605 · VCV16940

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1113 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CRYGD-related disorders

Computational evidence

Protein change
AlphaMissense	0.1113	likely benign ⚠ discordant with ClinVar
REVEL	0.51	indeterminate
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -5
Regional constraint	o/e 1.00	unconstrained · MANE · 2,797 bp · p 0.94 · regional, not allelic
Overall
CADD	0.274	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 0.0011% South Asian · 1/90,712 alleles

Overall 0.000124% 2/1,610,998 alleles · very rare exomes 2/1,458,632 · genomes 0/152,366 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,712
European (non-Finnish)	8.48e-05%	1,178,932

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: CRYGD
Protein: p.Pro24Thr
Coding: c.70C>A
MANE Select: NM_006891
dbSNP: rs28931605
Type: single nucleotide variant
Location: chr2:208124294 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.45 · 16 PDB
Residue 24: the beta/gamma crystallin 'greek key' 1 domain; a UniProt-annotated variant site (in ctrct4; reduces solubility); a UniProt-annotated variant site (in ctrct4; uncertain significance; reduces solubility)

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

Disease context

CRYGD-related disorders

Also linked: cataract 4 multiple types

Similar variants

CRYGD p.Pro24Ser Pathogenic ⚠ same residue
CRYGD p.Arg140Ter Pathogenic ★★ same condition
CRYGD p.Arg15Cys Pathogenic ★★ ⚠ same condition
CRYGD p.Arg37Pro Likely pathogenic ★★ same condition
CRYGD p.Asn161Ser Uncertain significance ★★ ⚠ same condition
CRYGD c.10-7C>G Benign ★★ same condition
CRYGD c.252+10T>A Benign/Likely benign ★★ same condition
CRYGD c.252+7A>G Benign ★★ 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/crygd-p-pro24thr (accessed [today's date]).

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