Is MERTK p.Ala740= (c.2220G>A) pathogenic?

MERTK p.Ala740= (c.2220G>A) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-05). Very rare (popmax 0.00446%, eas); Associated with retinitis pigmentosa 38.

What condition is associated with MERTK p.Ala740= (c.2220G>A)?

MERTK p.Ala740= (c.2220G>A) is associated with retinitis pigmentosa 38 (ClinVar).

How common is MERTK p.Ala740= (c.2220G>A) in the general population?

MERTK p.Ala740= (c.2220G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Retinitis pigmentosa inherited?

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

MERTK p.Ala740=

c.2220G>A · rs771592694 · VCV862734

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

retinitis pigmentosa 38

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.99	acceptor gain · deltas
Pangolin	Δ0.75	gain · loss 0.49 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -15	GERP -3.4
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000434% 7/1,613,646 alleles · very rare exomes 7/1,461,404 · genomes 0/152,242 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
South Asian	0.0022%	45,527
African / African-American	0.00133%	75,002
European (non-Finnish)	0.00017%	589,936

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: MERTK
Protein: p.Ala740=
Coding: c.2220G>A
MANE Select: NM_006343
dbSNP: rs771592694
Type: single nucleotide variant
Location: chr2:112021452 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 740: the protein kinase domain

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

Disease context

retinitis pigmentosa 38 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

MERTK p.Ala740Val Pathogenic ★ same residue
MERTK c.1296+1G>A Pathogenic/Likely pathogenic ★★ same condition
MERTK c.1605-2A>G Pathogenic ★★ same condition
MERTK c.1867+1G>A Likely pathogenic ★★ same condition
MERTK c.1868-1G>A Pathogenic ★★ same condition
MERTK c.2189+1G>T Pathogenic ★★ same condition
MERTK p.Ala768Val Likely pathogenic ★★ same condition
MERTK p.Arg651Ter 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/mertk-p-ala740 (accessed [today's date]).

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