Is MPC1 p.Arg76Gln (c.227G>A) pathogenic?

MPC1 p.Arg76Gln (c.227G>A) is classified Uncertain significance in MPC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-13). AlphaMissense: likely benign (0.3008); Very rare (popmax 0.00549%, sas).

How common is MPC1 p.Arg76Gln (c.227G>A) in the general population?

MPC1 p.Arg76Gln (c.227G>A) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about MPC1 p.Arg76Gln (c.227G>A)?

AlphaMissense predicts likely benign (score 0.3008) — an in-silico prediction, not a clinical call.

MPC1 p.Arg76Gln

c.227G>A · rs201142077 · VCV1380961

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3008 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3008	likely benign
REVEL	0.561	indeterminate
SaProt	LLR -10.61	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 0.31, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,410 bp · p 0.063 · regional, not allelic
Overall
CADD	25.8	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 0.00549% South Asian · 5/91,066 alleles

Filtering AF 0.00378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00397% 64/1,613,726 alleles · very rare exomes 58/1,461,636 · genomes 6/152,090 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,213
European (non-Finnish)	0.00483%	20,699
Remaining individualsnot grpmax-eligible	0.0016%	62,474
African / African-American	0.00134%	74,876

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.Arg76Gln
Coding: c.227G>A
MANE Select: NM_016098
dbSNP: rs201142077
Type: single nucleotide variant
Location: chr6:166366052 (GRCh38)
Gene constraint: LOEUF 0.919 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 92.85 · 13 PDB

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

Similar variants

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
MPC1 p.Ala70Thr Likely pathogenic ★ same type
MPC1 p.Arg97Gln Likely pathogenic ★ 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-arg76gln (accessed [today's date]).

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