Is SHMT2 p.Pro499Ala (c.1495C>G) pathogenic?

SHMT2 p.Pro499Ala (c.1495C>G) is classified Likely pathogenic in SHMT2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-27). AlphaMissense: likely pathogenic (0.578); Very rare (popmax 0.000255%, nfe); Associated with neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities.

How common is SHMT2 p.Pro499Ala (c.1495C>G) in the general population?

SHMT2 p.Pro499Ala (c.1495C>G) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about SHMT2 p.Pro499Ala (c.1495C>G)?

AlphaMissense predicts likely pathogenic (score 0.578) — an in-silico prediction, not a clinical call.

SHMT2 p.Pro499Ala

Q: What condition is associated with SHMT2 p.Pro499Ala (c.1495C>G)?

SHMT2 p.Pro499Ala (c.1495C>G) is associated with neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (ClinVar).

c.1495C>G · rs2037465152 · VCV988632

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.578 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities

Computational evidence

Protein change
AlphaMissense	0.578	likely pathogenic ✓ concordant with ClinVar
REVEL	0.613	indeterminate
SaProt	LLR -11.48	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,579 bp · p 8.5e-07 · regional, not allelic
Overall
CADD	26.2	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 0.000255% European (non-Finnish) · 3/1,176,828 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000249% 4/1,606,948 alleles · very rare exomes 4/1,454,646 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,170
European (non-Finnish)grpmax	0.000255%	392,275

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro499Ala
Coding: c.1495C>G
MANE Select: NM_005412
dbSNP: rs2037465152
Type: single nucleotide variant
Location: chr12:57234341 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.24 · 33 PDB
Residue 499: a UniProt-annotated variant site (in nedcasb; no effect on protein abundance; decreased glycine hydroxymethyltransferase activity; associated with altered mitochondrial redox metabolism)

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.Thr186Arg Likely pathogenic ★ same condition
SHMT2 c.857+19G>A Uncertain significance ★ same condition
SHMT2 p.Ala253Val 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-pro499ala (accessed [today's date]).

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