Is MERTK p.Phe538Val (c.1612T>G) pathogenic?

MERTK p.Phe538Val (c.1612T>G) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-28). AlphaMissense: ambiguous (0.5408); Very rare (popmax 0.0039%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MERTK p.Phe538Val (c.1612T>G)?

MERTK p.Phe538Val (c.1612T>G) is associated with Inborn genetic diseases (ClinVar).

How common is MERTK p.Phe538Val (c.1612T>G) in the general population?

MERTK p.Phe538Val (c.1612T>G) is very rare (popmax 0.0039%, nfe) (gnomAD).

What do computational predictors say about MERTK p.Phe538Val (c.1612T>G)?

AlphaMissense predicts ambiguous (score 0.5408) — an in-silico prediction, not a clinical call.

MERTK p.Phe538Val

c.1612T>G · VCV3294267

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0039%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5408	ambiguous
REVEL	0.583	indeterminate
SaProt	LLR -5.00	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	26.1	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 0.0039% European (non-Finnish) · 46/1,178,520 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00268%

Overall 0.00291% 47/1,612,498 alleles · very rare exomes 47/1,460,194 · genomes 0/152,304 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0039%	25,620
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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.Phe538Val
Coding: c.1612T>G
MANE Select: NM_006343
Type: single nucleotide variant
Location: chr2:112001208 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MERTK p.Ala29Gly Uncertain significance ★★ ⚠ same condition
MERTK p.Ala353Val Uncertain significance ★★ ⚠ same condition
MERTK p.Ala773Thr Uncertain significance ★★ ⚠ same condition
MERTK p.Ala944Thr Uncertain significance ★★ ⚠ same condition
MERTK p.Arg237Cys Uncertain significance ★★ ⚠ same condition
MERTK p.Arg557Gln Uncertain significance ★★ ⚠ same condition
MERTK p.Arg629Trp Uncertain significance ★★ ⚠ same condition
MERTK p.Arg796Gln Uncertain significance ★★ ⚠ 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-phe538val (accessed [today's date]).

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