Is RET p.Ser6Pro (c.16T>C) pathogenic?

RET p.Ser6Pro (c.16T>C) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-09). AlphaMissense: likely benign (0.1321); No allele count reported in gnomAD v4.1 (AN 1,506,524); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ser6Pro (c.16T>C)?

RET p.Ser6Pro (c.16T>C) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Ser6Pro (c.16T>C) in the general population?

RET p.Ser6Pro (c.16T>C) is no allele count reported in gnomAD v4.1 (AN 1,506,524) (gnomAD).

What do computational predictors say about RET p.Ser6Pro (c.16T>C)?

AlphaMissense predicts likely benign (score 0.1321) — an in-silico prediction, not a clinical call.

RET p.Ser6Pro

c.16T>C · rs1588848475 · VCV1011760

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1321 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,506,524)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1321	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -5.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.48, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 23 kb · p 0.39 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,506,524). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RET
Protein: p.Ser6Pro
Coding: c.16T>C
MANE Select: NM_020975
dbSNP: rs1588848475
Type: single nucleotide variant
Location: chr10:43077274 (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

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

Also linked: multiple endocrine neoplasia type 2

Similar variants

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
RET p.Arg77Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
RET p.Arg873Trp Likely pathogenic ★★ same condition
RET p.Arg897Ter Pathogenic ★★ same condition
RET p.Asp631Tyr Pathogenic ★★ ⚠ same condition
RET p.Cys609Arg 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-ser6pro (accessed [today's date]).

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