Is RET p.Ser561Arg (c.1683C>A) pathogenic?

RET p.Ser561Arg (c.1683C>A) is classified Uncertain significance in RET (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.8668); Very rare (popmax 0.000169%, nfe); Associated with multiple endocrine neoplasia type 2.

What condition is associated with RET p.Ser561Arg (c.1683C>A)?

RET p.Ser561Arg (c.1683C>A) is associated with multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Ser561Arg (c.1683C>A) in the general population?

RET p.Ser561Arg (c.1683C>A) is very rare (popmax 0.000169%, 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.Ser561Arg (c.1683C>A)?

AlphaMissense predicts likely pathogenic (score 0.8668) — an in-silico prediction, not a clinical call.

RET p.Ser561Arg

c.1683C>A · rs1837973045 · VCV1004827

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

multiple endocrine neoplasia type 2

Computational evidence

Protein change
AlphaMissense	0.8668	likely pathogenic
REVEL	0.458	indeterminate
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.23	GERP 0.94, phastCons 0.97
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	22.1	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 0.000169% European (non-Finnish) · 2/1,180,014 alleles

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

Overall 0.000186% 3/1,614,008 alleles · very rare exomes 2/1,461,806 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)grpmax	0.000169%	590,005

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser561Arg
Coding: c.1683C>A
MANE Select: NM_020975
dbSNP: rs1837973045
Type: single nucleotide variant
Location: chr10:43112887 (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.Ser561Asn Uncertain significance ★★ ⚠ same residue
RET p.Ser561Cys Uncertain significance ★★ ⚠ same residue
RET p.Ser561Gly Uncertain significance ★★ ⚠ same residue
RET p.Ser561Thr Uncertain significance ★ ⚠ same residue
RET p.Ser561= Likely benign ★ 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

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-ser561arg (accessed [today's date]).

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