Is CRX p.Ala121Val (c.362C>T) pathogenic?

CRX p.Ala121Val (c.362C>T) is classified Uncertain significance in CRX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.0881); Very rare (popmax 0.00891%, eas); Associated with cone-rod dystrophy 2.

What condition is associated with CRX p.Ala121Val (c.362C>T)?

CRX p.Ala121Val (c.362C>T) is associated with cone-rod dystrophy 2, Leber congenital amaurosis 7 (ClinVar).

How common is CRX p.Ala121Val (c.362C>T) in the general population?

CRX p.Ala121Val (c.362C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

How is Cone rod dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CRX p.Ala121Val (c.362C>T)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

CRX p.Ala121Val

c.362C>T · rs371847743 · VCV2138313

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cone-rod dystrophy 2

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.77	donor gain · deltas
Pangolin	Δ0.68	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.2	GERP 0.49, phastCons 0.98
Regional constraint	o/e 0.94	unconstrained · MANE · 622 bp · p 0.35 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,890 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000991% 16/1,613,732 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,223
Remaining individualsnot grpmax-eligible	0.0032%	31,237
South Asian	0.0022%	45,546
Admixed American	0.00167%	59,972
European (non-Finnish)	0.000593%	168,552

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: CRX
Protein: p.Ala121Val
Coding: c.362C>T
MANE Select: NM_000554
dbSNP: rs371847743
Type: single nucleotide variant
Location: chr19:47839429 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI 0.72 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 61.78 · 1 PDB
Residue 121: the 'disordered' region

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

Disease context

cone-rod dystrophy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leber congenital amaurosis 7

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CRX p.Ala121= Likely benign ★★ 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.Arg43Cys Pathogenic ★★ same condition
CRX p.Arg43His Pathogenic/Likely pathogenic ★★ same condition
CRX p.Arg69Cys Pathogenic/Likely 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-ala121val (accessed [today's date]).

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