Is CRX p.Ile138Val (c.412A>G) pathogenic?

CRX p.Ile138Val (c.412A>G) is classified Uncertain significance in CRX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-27). AlphaMissense: likely benign (0.0981); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with CRX p.Ile138Val (c.412A>G)?

CRX p.Ile138Val (c.412A>G) is associated with Inborn genetic diseases, cone-rod dystrophy 2, Leber congenital amaurosis 7 (ClinVar).

How common is CRX p.Ile138Val (c.412A>G) in the general population?

CRX p.Ile138Val (c.412A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CRX p.Ile138Val (c.412A>G)?

AlphaMissense predicts likely benign (score 0.0981) — an in-silico prediction, not a clinical call.

CRX p.Ile138Val

c.412A>G · rs373934471 · VCV1349400

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0981	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -4.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -3.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 622 bp · p 0.35 · regional, not allelic
Overall
CADD	14.11	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 0.00267% African / African-American · 2/74,988 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000205% 3/1,461,794 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,494
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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.Ile138Val
Coding: c.412A>G
MANE Select: NM_000554
dbSNP: rs373934471
Type: single nucleotide variant
Location: chr19:47839479 (GRCh38)
Gene constraint: LOEUF 0.673 · pLI 0.72 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 61.78 · 1 PDB
Residue 138: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

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
CRX p.Arg69His 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-ile138val (accessed [today's date]).

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