Is MERTK p.Arg557Pro (c.1670G>C) pathogenic?

MERTK p.Arg557Pro (c.1670G>C) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-25). AlphaMissense: likely pathogenic (0.5931); Ultra-rare (popmax 0.0111%, eas); Associated with retinitis pigmentosa 38.

What condition is associated with MERTK p.Arg557Pro (c.1670G>C)?

MERTK p.Arg557Pro (c.1670G>C) is associated with retinitis pigmentosa 38 (ClinVar).

How common is MERTK p.Arg557Pro (c.1670G>C) in the general population?

MERTK p.Arg557Pro (c.1670G>C) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

How is Retinitis pigmentosa inherited?

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

What do computational predictors say about MERTK p.Arg557Pro (c.1670G>C)?

AlphaMissense predicts likely pathogenic (score 0.5931) — an in-silico prediction, not a clinical call.

MERTK p.Arg557Pro

c.1670G>C · rs374078768 · VCV866874

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5931 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa 38

Computational evidence

Protein change
AlphaMissense	0.5931	likely pathogenic
REVEL	0.716	pathogenic-leaning
SaProt	LLR -6.59	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	32.0	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 0.0111% East Asian · 5/44,886 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.00212% 31/1,461,400 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0384%	2,604
East Asiangrpmax	0.0111%	8,977
South Asian	0.0011%	91,064
European (non-Finnish)	8.48e-05%	1,179,618

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg557Pro
Coding: c.1670G>C
MANE Select: NM_006343
dbSNP: rs374078768
Type: single nucleotide variant
Location: chr2:112001266 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB

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.Arg557Gln Uncertain significance ★★ ⚠ same residue
MERTK p.Arg557Trp Uncertain significance ★★ ⚠ 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

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-arg557pro (accessed [today's date]).

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