Is RET p.Ser518Phe (c.1553C>T) pathogenic?

RET p.Ser518Phe (c.1553C>T) is classified Uncertain significance in RET (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-25). AlphaMissense: ambiguous (0.5242); Very rare (popmax 0.00017%, nfe); Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Ser518Phe (c.1553C>T)?

RET p.Ser518Phe (c.1553C>T) is associated with multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Ser518Phe (c.1553C>T) in the general population?

RET p.Ser518Phe (c.1553C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RET p.Ser518Phe (c.1553C>T)?

AlphaMissense predicts ambiguous (score 0.5242) — an in-silico prediction, not a clinical call.

RET p.Ser518Phe

c.1553C>T · rs2132797325 · VCV1504488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
AlphaMissense	0.5242	ambiguous
REVEL	0.719	pathogenic-leaning
SaProt	LLR -8.77	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	27.7	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 0.00017% European (non-Finnish) · 2/1,173,860 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,601,066 alleles · very rare exomes 2/1,448,688 · genomes 0/152,378 · 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: RET
Protein: p.Ser518Phe
Coding: c.1553C>T
MANE Select: NM_020975
dbSNP: rs2132797325
Type: single nucleotide variant
Location: chr10:43112129 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB

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

Disease context

multiple endocrine neoplasia type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple endocrine neoplasia type 2 (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RET p.Ser518Tyr Uncertain significance ★★ ⚠ same residue
RET p.Ser518= Likely benign ★★ same residue
RET p.Ser518Thr Uncertain significance ★ ⚠ same residue
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter Pathogenic ★★ same condition
RET p.Arg77Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
RET p.Arg897Ter Pathogenic ★★ same condition
RET p.Asp631Tyr 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/ret-p-ser518phe (accessed [today's date]).

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