Is MERTK p.Pro5Leu (c.14C>T) pathogenic?

MERTK p.Pro5Leu (c.14C>T) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-30). AlphaMissense: likely benign (0.151); Very rare (popmax 0.00935%, afr).

How common is MERTK p.Pro5Leu (c.14C>T) in the general population?

MERTK p.Pro5Leu (c.14C>T) is very rare (popmax 0.00935%, afr) (gnomAD).

What do computational predictors say about MERTK p.Pro5Leu (c.14C>T)?

AlphaMissense predicts likely benign (score 0.151) — an in-silico prediction, not a clinical call.

MERTK p.Pro5Leu

c.14C>T · rs766821604 · VCV1064131

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.151 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00935%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.151	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.84	GERP -2.4
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	7.259	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 0.00935% African / African-American · 7/74,838 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.00125% 20/1,606,020 alleles · very rare exomes 15/1,453,850 · genomes 5/152,170 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00935%	10,691
Remaining individualsnot grpmax-eligible	0.00161%	62,022
European (non-Finnish)	0.00102%	98,083

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.Pro5Leu
Coding: c.14C>T
MANE Select: NM_006343
dbSNP: rs766821604
Type: single nucleotide variant
Location: chr2:111898749 (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

Similar variants

MERTK p.Pro5Arg Uncertain significance ★ ⚠ same residue
MERTK p.Pro5= Likely benign ★ same residue
MERTK p.Pro5fs Pathogenic ★ same residue
MERTK c.1296+1G>A Pathogenic/Likely pathogenic ★★ same type
MERTK c.1605-2A>G Pathogenic ★★ same type
MERTK c.1787-2A>T Pathogenic/Likely pathogenic ★★ same type
MERTK c.1867+1G>A Likely pathogenic ★★ same type
MERTK c.1868-1G>A Pathogenic ★★ same type

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-pro5leu (accessed [today's date]).

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