Is RET p.Ser904Phe (c.2711C>T) pathogenic?

RET p.Ser904Phe (c.2711C>T) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-17). AlphaMissense: ambiguous (0.5149); Very rare (popmax 6.2e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ser904Phe (c.2711C>T)?

RET p.Ser904Phe (c.2711C>T) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2A (ClinVar).

How common is RET p.Ser904Phe (c.2711C>T) in the general population?

RET p.Ser904Phe (c.2711C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about RET p.Ser904Phe (c.2711C>T)?

AlphaMissense predicts ambiguous (score 0.5149) — an in-silico prediction, not a clinical call.

RET p.Ser904Phe

c.2711C>T · rs267607011 · VCV24963

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5149 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5149	ambiguous
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -9.65	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1, phastCons 1
Regional constraint	o/e 0.47	unconstrained · MANE · 4,087 bp · p 2.5e-11 · regional, not allelic
Overall
CADD	29.4	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 6.2e-05%

Overall 6.2e-05% 1/1,613,158 alleles · very rare exomes 1/1,460,846 · genomes 0/152,312 · 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.Ser904Phe
Coding: c.2711C>T
MANE Select: NM_020975
dbSNP: rs267607011
Type: single nucleotide variant
Location: chr10:43120184 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple endocrine neoplasia type 2A

Similar variants

RET p.Ser904Ala Uncertain significance ★★ ⚠ same residue
RET p.Ser904= Benign/Likely benign ★★ same residue
RET p.Ser904Leu Uncertain significance ★★ same residue
RET p.Ser904_Tyr905= Benign ★ same residue
RET p.Ser904Cys Uncertain significance ★★ ⚠ same residue
RET c.1759+1G>A Pathogenic/Likely pathogenic ★★ same condition
RET p.Arg873Trp Likely 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-ser904phe (accessed [today's date]).

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