Is RET p.Val311= (c.933G>A) pathogenic?

RET p.Val311= (c.933G>A) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-30). Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with RET p.Val311= (c.933G>A)?

RET p.Val311= (c.933G>A) is associated with hereditary neoplastic syndrome, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2 (ClinVar).

How common is RET p.Val311= (c.933G>A) in the general population?

RET p.Val311= (c.933G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

RET p.Val311=

c.933G>A · rs1210305963 · VCV762696

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.60	donor gain · deltas
Pangolin	Δ0.39	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.2	GERP -1.8, phastCons 0.99
Overall
CADD	17.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Overall 0.000124% 2/1,613,446 alleles · very rare exomes 1/1,461,240 · genomes 1/152,206 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	8.48e-05%	1,179,869

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.Val311=
Coding: c.933G>A
MANE Select: NM_020975
dbSNP: rs1210305963
Type: single nucleotide variant
Location: chr10:43106441 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 311: the 'cadherin-like region 3 (cld3)' 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: multiple endocrine neoplasia type 2A multiple endocrine neoplasia type 2

Similar variants

RET p.Val311Leu Uncertain significance ★★ ⚠ same residue
RET p.Val311Met 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.Arg897Ter 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-val311 (accessed [today's date]).

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