Is RET p.Val438Ile (c.1312G>A) pathogenic?

RET p.Val438Ile (c.1312G>A) is classified Conflicting classifications of pathogenicity in RET (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.0655); Very rare (popmax 0.004%, afr); Associated with RET-related disorder.

What condition is associated with RET p.Val438Ile (c.1312G>A)?

RET p.Val438Ile (c.1312G>A) is associated with RET-related disorder, Hirschsprung disease, susceptibility to, 1, familial medullary thyroid carcinoma (ClinVar).

How common is RET p.Val438Ile (c.1312G>A) in the general population?

RET p.Val438Ile (c.1312G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about RET p.Val438Ile (c.1312G>A)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

RET p.Val438Ile

c.1312G>A · rs774474422 · VCV477314

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RET-related disorder

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.52	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 -0.6	GERP -4.3
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.00012 · regional, not allelic
Overall
CADD	2.939	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 0.004% African / African-American · 3/74,940 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00118% 19/1,614,044 alleles · very rare exomes 14/1,461,812 · genomes 5/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,980
Admixed American	0.00333%	30,003
Finnishnot grpmax-eligible	0.00313%	31,987
South Asian	0.0022%	45,543
European (non-Finnish)	0.000847%	118,005

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.Val438Ile
Coding: c.1312G>A
MANE Select: NM_020975
dbSNP: rs774474422
Type: single nucleotide variant
Location: chr10:43111255 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.27 · 34 PDB
Residue 438: the 'cadherin-like region 4 (cld4)' region

Full RET gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RET-related disorder

Also linked: Hirschsprung disease, susceptibility to, 1 familial medullary thyroid carcinoma multiple endocrine neoplasia type 2B pheochromocytoma multiple endocrine neoplasia type 2A hereditary neoplastic syndrome multiple endocrine neoplasia type 2

Similar variants

RET p.Val438= Likely benign ★★ same residue
RET p.Val438Phe 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-val438ile (accessed [today's date]).

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