Is RET p.Ser462Leu (c.1385C>T) pathogenic?

RET p.Ser462Leu (c.1385C>T) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.1438); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Ser462Leu (c.1385C>T)?

RET p.Ser462Leu (c.1385C>T) is associated with hereditary neoplastic syndrome, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Ser462Leu (c.1385C>T) in the general population?

RET p.Ser462Leu (c.1385C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about RET p.Ser462Leu (c.1385C>T)?

AlphaMissense predicts likely benign (score 0.1438) — an in-silico prediction, not a clinical call.

RET p.Ser462Leu

c.1385C>T · rs1313331250 · VCV956150

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1438 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1438	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -6.28	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 1.4	GERP -1.2, phastCons 0.002
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	15.69	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 0.0011% South Asian · 1/91,088 alleles

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

Overall 0.000186% 3/1,614,136 alleles · very rare exomes 3/1,461,782 · genomes 0/152,354 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,088
European (non-Finnish)	0.000169%	590,026

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.Ser462Leu
Coding: c.1385C>T
MANE Select: NM_020975
dbSNP: rs1313331250
Type: single nucleotide variant
Location: chr10:43111328 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 462: the 'cadherin-like region 4 (cld4)' region

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: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma multiple endocrine neoplasia type 2B ovarian cancer pheochromocytoma multiple endocrine neoplasia type 2A multiple endocrine neoplasia type 2

Similar variants

RET p.Ser462= Likely benign ★★ same residue
RET p.Ser462Trp Uncertain significance ★ ⚠ 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
RET p.Arg77Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
RET p.Arg873Trp Likely pathogenic ★★ same condition
RET p.Arg897Gln 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-ser462leu (accessed [today's date]).

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