Is MERTK p.Ser312Phe (c.935C>T) pathogenic?

MERTK p.Ser312Phe (c.935C>T) is classified Likely pathogenic in MERTK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-09). AlphaMissense: ambiguous (0.5017); Very rare (popmax 0.000593%, nfe); Associated with MERTK-related disorder.

What condition is associated with MERTK p.Ser312Phe (c.935C>T)?

MERTK p.Ser312Phe (c.935C>T) is associated with MERTK-related disorder (ClinVar).

How common is MERTK p.Ser312Phe (c.935C>T) in the general population?

MERTK p.Ser312Phe (c.935C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about MERTK p.Ser312Phe (c.935C>T)?

AlphaMissense predicts ambiguous (score 0.5017) — an in-silico prediction, not a clinical call.

MERTK p.Ser312Phe

c.935C>T · VCV4956492

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5017 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

MERTK-related disorder

Computational evidence

Protein change
AlphaMissense	0.5017	ambiguous
REVEL	0.397	indeterminate
SaProt	LLR -10.55	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 130 kb · p 0.00043 · regional, not allelic
Overall
CADD	27.3	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 0.000593% European (non-Finnish) · 7/1,179,784 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,782 alleles · very rare exomes 7/1,461,650 · genomes 0/152,132 · joint denominator

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.Ser312Phe
Coding: c.935C>T
MANE Select: NM_006343
Type: single nucleotide variant
Location: chr2:111968227 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.78 · 42 PDB
Residue 312: the fibronectin type-iii 1 domain

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

Disease context

MERTK-related disorder

Similar variants

MERTK p.Ser312fs Likely pathogenic ★ same residue
MERTK c.1605-2A>G Pathogenic ★★ same condition
MERTK c.1787-2A>T Pathogenic/Likely pathogenic ★★ same condition
MERTK c.2189+1G>T Pathogenic ★★ same condition
MERTK p.Ala768Thr Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Ala768Val Likely pathogenic ★★ same condition
MERTK p.Arg558Ter Pathogenic/Likely pathogenic ★★ same condition
MERTK p.Arg651Ter 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-ser312phe (accessed [today's date]).

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