Is CRX p.Ala92Thr (c.274G>A) pathogenic?

CRX p.Ala92Thr (c.274G>A) is classified Conflicting classifications of pathogenicity in CRX (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-06-28). AlphaMissense: likely pathogenic (0.9973); Absent from gnomAD v4.1; Associated with CRX-related disorders.

What condition is associated with CRX p.Ala92Thr (c.274G>A)?

CRX p.Ala92Thr (c.274G>A) is associated with CRX-related disorders, cone-rod dystrophy 2, Leber congenital amaurosis 7 (ClinVar).

How common is CRX p.Ala92Thr (c.274G>A) in the general population?

CRX p.Ala92Thr (c.274G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CRX p.Ala92Thr (c.274G>A)?

AlphaMissense predicts likely pathogenic (score 0.9973) — an in-silico prediction, not a clinical call.

CRX p.Ala92Thr

c.274G>A · rs786205521 · VCV191106

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9973 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CRX-related disorders

Computational evidence

Protein change
AlphaMissense	0.9973	likely pathogenic · top 7% in CRX
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -14.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.18	constrained · MANE · 2,963 bp · p 0.00074 · regional, not allelic
Overall
CADD	29.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CRX
Protein: p.Ala92Thr
Coding: c.274G>A
MANE Select: NM_000554
dbSNP: rs786205521
Type: single nucleotide variant
Location: chr19:47839341 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI 0.72 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 61.78 · 1 PDB
Residue 92: a DNA-binding region; an α-helix

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

Disease context

CRX-related disorders

Also linked: cone-rod dystrophy 2 Leber congenital amaurosis 7

Similar variants

CRX p.Ala92= Benign/Likely benign ★★ same residue
CRX p.Ala92Pro Uncertain significance ★ ⚠ same residue
CRX c.101-1G>A Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg40Gln Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg40Trp Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg41Gln Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg41Pro Likely pathogenic ★★ same condition
CRX p.Arg43Cys Pathogenic ★★ 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/crx-p-ala92thr (accessed [today's date]).

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