Is SHMT2 p.Ala253Val (c.758C>T) pathogenic?

SHMT2 p.Ala253Val (c.758C>T) is classified Uncertain significance in SHMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-11). AlphaMissense: likely pathogenic (0.972); No allele count reported in gnomAD v4.1 (AN 1,612,744); Associated with neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities.

How common is SHMT2 p.Ala253Val (c.758C>T) in the general population?

SHMT2 p.Ala253Val (c.758C>T) is no allele count reported in gnomAD v4.1 (AN 1,612,744) (gnomAD).

What do computational predictors say about SHMT2 p.Ala253Val (c.758C>T)?

AlphaMissense predicts likely pathogenic (score 0.972) — an in-silico prediction, not a clinical call.

SHMT2 p.Ala253Val

Q: What condition is associated with SHMT2 p.Ala253Val (c.758C>T)?

SHMT2 p.Ala253Val (c.758C>T) is associated with neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (ClinVar).

c.758C>T · rs2548103874 · VCV3237524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.972 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,612,744)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities

Computational evidence

Protein change
AlphaMissense	0.972	likely pathogenic
REVEL	0.529	indeterminate
SaProt	LLR -13.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,579 bp · p 8.5e-07 · regional, not allelic
Overall
CADD	29.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,612,744). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SHMT2
Protein: p.Ala253Val
Coding: c.758C>T
MANE Select: NM_005412
dbSNP: rs2548103874
Type: single nucleotide variant
Location: chr12:57232744 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.24 · 33 PDB
Residue 253: an α-helix

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

Disease context

neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SHMT2 p.Arg25Gln Uncertain significance ★★ ⚠ same condition
SHMT2 p.Arg359Trp Uncertain significance ★★ ⚠ same condition
SHMT2 p.Arg488Trp Uncertain significance ★★ ⚠ same condition
SHMT2 p.Asn379Asp Likely pathogenic ★ same condition
SHMT2 p.Pro499Ala Likely pathogenic ★ same condition
SHMT2 p.Thr186Arg Likely pathogenic ★ same condition
SHMT2 c.857+19G>A Uncertain significance ★ same condition
SHMT2 p.Arg217Gln 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-ala253val (accessed [today's date]).

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