Is MERTK p.Ile174Phe (c.520A>T) pathogenic?

MERTK p.Ile174Phe (c.520A>T) is classified Uncertain significance in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-03). AlphaMissense: likely benign (0.0683); Ultra-rare (popmax 0.0187%, sas); Associated with retinitis pigmentosa 38.

What condition is associated with MERTK p.Ile174Phe (c.520A>T)?

MERTK p.Ile174Phe (c.520A>T) is associated with retinitis pigmentosa 38 (ClinVar).

How common is MERTK p.Ile174Phe (c.520A>T) in the general population?

MERTK p.Ile174Phe (c.520A>T) is ultra-rare (popmax 0.0187%, sas) (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.Ile174Phe (c.520A>T)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

MERTK p.Ile174Phe

c.520A>T · rs775179251 · VCV811179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa 38

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -7.98	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 0.052	GERP -5
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	1.459	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 0.0187% South Asian · 17/91,084 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.0013% 19/1,461,512 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Ile174Phe
Coding: c.520A>T
MANE Select: NM_006343
dbSNP: rs775179251
Type: single nucleotide variant
Location: chr2:111944997 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 174: a disulfide bond; the ig-like c2-type 1 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 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
MERTK p.Arg722Ter 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-ile174phe (accessed [today's date]).

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