Is MERTK p.Ala740Val (c.2219C>T) pathogenic?

MERTK p.Ala740Val (c.2219C>T) is classified Pathogenic in MERTK (ClinVar, Single submitter, 2 submitters; last evaluated 2021-11-26). AlphaMissense: likely pathogenic (0.9881); Very rare (popmax 0.00167%, amr); Associated with MERTK-related disorder.

What condition is associated with MERTK p.Ala740Val (c.2219C>T)?

MERTK p.Ala740Val (c.2219C>T) is associated with MERTK-related disorder (ClinVar).

How common is MERTK p.Ala740Val (c.2219C>T) in the general population?

MERTK p.Ala740Val (c.2219C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MERTK p.Ala740Val (c.2219C>T)?

AlphaMissense predicts likely pathogenic (score 0.9881) — an in-silico prediction, not a clinical call.

MERTK p.Ala740Val

c.2219C>T · rs911057284 · VCV979015

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MERTK-related disorder

Computational evidence

Protein change
AlphaMissense	0.9881	likely pathogenic ✓ concordant with ClinVar · top 4% in MERTK
REVEL	0.797	moderately pathogenic-leaning
SaProt	LLR -13.86	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 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	33.0	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 0.00167% Admixed American · 1/60,010 alleles

Overall 0.000137% 2/1,461,350 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
European (non-Finnish)	8.48e-05%	1,179,870

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.Ala740Val
Coding: c.2219C>T
MANE Select: NM_006343
dbSNP: rs911057284
Type: single nucleotide variant
Location: chr2:112021451 (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

MERTK-related disorder

Similar variants

MERTK p.Ala740= Uncertain significance ★★ same residue
MERTK c.1605-2A>G Pathogenic ★★ same condition
MERTK c.1787-2A>T Pathogenic/Likely pathogenic ★★ same condition
MERTK c.2189+1G>T Pathogenic ★★ same condition
MERTK p.Ala768Thr Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Ala768Val Likely pathogenic ★★ same condition
MERTK p.Arg558Ter Pathogenic/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-ala740val (accessed [today's date]).

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