Is MERTK p.Arg727Ter (c.2179C>T) pathogenic?

MERTK p.Arg727Ter (c.2179C>T) is classified Pathogenic in MERTK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-25). Very rare (popmax 0.00223%, eas); Associated with MERTK-related disorder.

What condition is associated with MERTK p.Arg727Ter (c.2179C>T)?

MERTK p.Arg727Ter (c.2179C>T) is associated with MERTK-related disorder, inherited retinal dystrophy (ClinVar).

How common is MERTK p.Arg727Ter (c.2179C>T) in the general population?

MERTK p.Arg727Ter (c.2179C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

MERTK p.Arg727Ter

c.2179C>T · rs746238212 · VCV866075

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

MERTK-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 19
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.9	GERP 0.91, phastCons 1
Overall
CADD	48.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000621% 10/1,610,372 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
Finnishnot grpmax-eligible	0.00156%	64,012
African / African-American	0.00134%	74,812
European (non-Finnish)	0.000595%	168,107

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.Arg727Ter
Coding: c.2179C>T
MANE Select: NM_006343
dbSNP: rs746238212
Type: single nucleotide variant
Location: chr2:112019512 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 727: the protein kinase domain; an α-helix

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

Disease context

MERTK-related disorder

Also linked: inherited retinal dystrophy

Similar variants

MERTK p.Arg727Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MERTK p.Arg727Gly Likely pathogenic 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

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-arg727ter (accessed [today's date]).

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