Is RET p.Ser904= (c.2712C>A) pathogenic?

RET p.Ser904= (c.2712C>A) is classified Benign/Likely benign in RET (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-13). Ultra-rare (popmax 0.01%, amr); Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Ser904= (c.2712C>A)?

RET p.Ser904= (c.2712C>A) is associated with multiple endocrine neoplasia type 2, multiple endocrine neoplasia type 2A, hereditary neoplastic syndrome (ClinVar).

How common is RET p.Ser904= (c.2712C>A) in the general population?

RET p.Ser904= (c.2712C>A) is ultra-rare (popmax 0.01%, amr) (gnomAD).

How is Multiple endocrine neoplasia type 2 inherited?

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

RET p.Ser904=

c.2712C>A · rs1800863 · VCV1558816

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.2	GERP -2.7
Overall
CADD	8.292	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,926 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.000685% 10/1,460,558 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,988
European (non-Finnish)	0.000339%	294,969

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.Ser904=
Coding: c.2712C>A
MANE Select: NM_020975
dbSNP: rs1800863
Type: single nucleotide variant
Location: chr10:43120185 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 904: the protein kinase domain

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

Also linked: multiple endocrine neoplasia type 2A hereditary neoplastic syndrome

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.Ser904Ala Uncertain significance ★★ ⚠ same residue
RET p.Ser904Cys Uncertain significance ★★ ⚠ same residue
RET p.Ser904Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
RET p.Ser904Leu Uncertain significance ★★ same residue
RET p.Ser904_Tyr905= Benign ★ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET c.1879+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg180Ter 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-ser904 (accessed [today's date]).

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