Is MERTK p.Pro481Ser (c.1441C>T) pathogenic?

MERTK p.Pro481Ser (c.1441C>T) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-08-29). AlphaMissense: likely benign (0.1825); Ultra-rare (popmax 0.0579%, eas); Associated with inherited retinal dystrophy.

What condition is associated with MERTK p.Pro481Ser (c.1441C>T)?

MERTK p.Pro481Ser (c.1441C>T) is associated with inherited retinal dystrophy, retinitis pigmentosa (ClinVar).

How common is MERTK p.Pro481Ser (c.1441C>T) in the general population?

MERTK p.Pro481Ser (c.1441C>T) is ultra-rare (popmax 0.0579%, eas) (gnomAD).

What do computational predictors say about MERTK p.Pro481Ser (c.1441C>T)?

AlphaMissense predicts likely benign (score 0.1825) — an in-silico prediction, not a clinical call.

MERTK p.Pro481Ser

c.1441C>T · rs781442827 · VCV330757

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1825 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0579%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1825	likely benign
REVEL	0.429	indeterminate
SaProt	LLR -8.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	23.3	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 0.0579% East Asian · 26/44,882 alleles

Filtering AF 0.0405% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0347%

Overall 0.00211% 34/1,613,926 alleles · ultra-rare exomes 30/1,461,856 · genomes 4/152,070 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0579%	1,726
Remaining individualsnot grpmax-eligible	0.0096%	10,413
Admixed American	0.00167%	59,994
South Asian	0.0011%	91,074

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.Pro481Ser
Coding: c.1441C>T
MANE Select: NM_006343
dbSNP: rs781442827
Type: single nucleotide variant
Location: chr2:111994395 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 481: the fibronectin type-iii 2 domain

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa

Similar variants

MERTK c.1296+1G>A Pathogenic/Likely pathogenic ★★ same condition
MERTK c.2189+1G>T Pathogenic ★★ same condition
MERTK p.Ala768Thr Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Arg651Ter Pathogenic ★★ same condition
MERTK p.Arg687Ter Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Arg722Ter Pathogenic ★★ same condition
MERTK p.Arg727Ter Pathogenic ★★ same condition
MERTK p.Arg732Ter 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-pro481ser (accessed [today's date]).

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