Is SHMT2 p.Asp439Val (c.1316A>T) pathogenic?

SHMT2 p.Asp439Val (c.1316A>T) is classified Uncertain significance in SHMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.1154); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with SHMT2 p.Asp439Val (c.1316A>T)?

SHMT2 p.Asp439Val (c.1316A>T) is associated with Inborn genetic diseases (ClinVar).

How common is SHMT2 p.Asp439Val (c.1316A>T) in the general population?

SHMT2 p.Asp439Val (c.1316A>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SHMT2 p.Asp439Val (c.1316A>T)?

AlphaMissense predicts likely benign (score 0.1154) — an in-silico prediction, not a clinical call.

SHMT2 p.Asp439Val

c.1316A>T · VCV4164848

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1154 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1154	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,579 bp · p 8.5e-07 · regional, not allelic
Overall
CADD	21.3	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 · 1/91,082 alleles

Overall 0.000137% 2/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,025

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: SHMT2
Protein: p.Asp439Val
Coding: c.1316A>T
MANE Select: NM_005412
Type: single nucleotide variant
Location: chr12:57234039 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.24 · 33 PDB
Residue 439: an α-helix

Full SHMT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SHMT2 p.Arg230His Uncertain significance ★★ same condition
SHMT2 p.Arg25Gln Uncertain significance ★★ ⚠ same condition
SHMT2 p.Arg442Trp Uncertain significance ★★ ⚠ same condition
SHMT2 p.Arg488Trp Uncertain significance ★★ ⚠ same condition
SHMT2 p.Arg82Leu Uncertain significance ★★ ⚠ same condition
SHMT2 p.Asp378His Uncertain significance ★★ ⚠ same condition
SHMT2 p.Gly143Arg Uncertain significance ★★ ⚠ same condition
SHMT2 p.Val150Ile Uncertain significance ★★ ⚠ 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/shmt2-p-asp439val (accessed [today's date]).

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