Is SHMT2 p.Asp179= (c.537C>T) pathogenic?

SHMT2 p.Asp179= (c.537C>T) is classified Benign in SHMT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-05). Common (popmax 9.21%, eas) — too common for a highly-penetrant pathogenic allele.

SHMT2 p.Asp179=

Q: How common is SHMT2 p.Asp179= (c.537C>T) in the general population?

SHMT2 p.Asp179= (c.537C>T) is common (popmax 9.21%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.537C>T · rs11557166 · VCV1248932

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 9.21%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.047	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.85	GERP -4.8, phastCons 0.012
Overall
CADD	12.27	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.21% East Asian · 4,134/44,884 alleles

Filtering AF 8.98% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.88%

Overall 1.15% 18,530/1,614,094 alleles · common exomes 15,986/1,461,788 · genomes 2,544/152,306 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	9.21%	11
African / African-American	3.45%	29
South Asian	1.83%	55
Middle Eastern	1.29%	78
Remaining individualsnot grpmax-eligible	1.26%	79
European (non-Finnish)	0.744%	134
Ashkenazi Jewishnot grpmax-eligible	0.524%	191
Admixed American	0.421%	237
Finnishnot grpmax-eligible	0.147%	681

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.Asp179=
Coding: c.537C>T
MANE Select: NM_005412
dbSNP: rs11557166
Type: single nucleotide variant
Location: chr12:57232235 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.24 · 33 PDB
Residue 179: a β-strand

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

Similar variants

SHMT2 p.Arg230His Uncertain significance ★★ same type
SHMT2 p.Arg25Gln Uncertain significance ★★ ⚠ same type
SHMT2 p.Arg359Trp Uncertain significance ★★ ⚠ same type
SHMT2 p.Arg434Ter Uncertain significance ★★ same type
SHMT2 p.Arg442Trp Uncertain significance ★★ ⚠ same type
SHMT2 p.Arg488Trp Uncertain significance ★★ ⚠ same type
SHMT2 p.Arg82Leu Uncertain significance ★★ ⚠ same type
SHMT2 p.Asp378His Uncertain significance ★★ ⚠ same type

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-asp179 (accessed [today's date]).

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