Is MPC1 p.Thr25= (c.75G>A) pathogenic?

MPC1 p.Thr25= (c.75G>A) is classified Uncertain significance in MPC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-01). Very rare (popmax 0.00242%, eas).

How common is MPC1 p.Thr25= (c.75G>A) in the general population?

MPC1 p.Thr25= (c.75G>A) is very rare (popmax 0.00242%, eas) (gnomAD).

MPC1 p.Thr25=

c.75G>A · VCV4894824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00242%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.79	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.64	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.8	GERP 1.7, phastCons 1
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00242% East Asian · 1/41,254 alleles

Filtering AF 0.000191% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.3e-05%

Overall 0.00077% 6/779,270 alleles · very rare exomes 5/627,170 · genomes 1/152,100 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00285%	35,094
East Asiangrpmax	0.00242%	41,254
African / African-American	0.00169%	59,038
European (non-Finnish)	0.000719%	139,134

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: MPC1
Protein: p.Thr25=
Coding: c.75G>A
MANE Select: NM_016098
Type: single nucleotide variant
Location: chr6:166370218 (GRCh38)
Gene constraint: LOEUF 0.919 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 92.85 · 13 PDB
Residue 25: an α-helix

Full MPC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MPC1 p.Thr25Met Uncertain significance ★ ⚠ same residue
MPC1 p.Arg76Gln Uncertain significance ★★ ⚠ same type
MPC1 p.Glu102Lys Uncertain significance ★★ ⚠ same type
MPC1 p.Thr106Met Uncertain significance ★★ ⚠ same type
MPC1 c.72-8C>T Likely benign ★★ same type
MPC1 p.Ala10= Benign/Likely benign ★★ same type
MPC1 p.His101= Benign ★★ same type
MPC1 p.Leu36Ile Benign ★★ 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/mpc1-p-thr25 (accessed [today's date]).

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