Is MERTK p.Thr212Pro (c.634A>C) pathogenic?

MERTK p.Thr212Pro (c.634A>C) is classified Uncertain significance in MERTK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-26). AlphaMissense: ambiguous (0.5125); Very rare (popmax 0.00398%, nfe); Associated with retinitis pigmentosa 38.

What condition is associated with MERTK p.Thr212Pro (c.634A>C)?

MERTK p.Thr212Pro (c.634A>C) is associated with retinitis pigmentosa 38 (ClinVar).

How common is MERTK p.Thr212Pro (c.634A>C) in the general population?

MERTK p.Thr212Pro (c.634A>C) is very rare (popmax 0.00398%, nfe) (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.Thr212Pro (c.634A>C)?

AlphaMissense predicts ambiguous (score 0.5125) — an in-silico prediction, not a clinical call.

MERTK p.Thr212Pro

c.634A>C · rs2104704629 · VCV1698891

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5125 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

retinitis pigmentosa 38

Computational evidence

Protein change
AlphaMissense	0.5125	ambiguous
REVEL	0.188	benign-leaning
SaProt	LLR -12.25	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	24.4	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 0.00398% European (non-Finnish) · 47/1,180,030 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00322% 47/1,461,886 alleles · very rare

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.Thr212Pro
Coding: c.634A>C
MANE Select: NM_006343
dbSNP: rs2104704629
Type: single nucleotide variant
Location: chr2:111947444 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 212: the ig-like c2-type 2 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-thr212pro (accessed [today's date]).

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