Is MACROD2 p.Trp43Arg (c.127T>C) pathogenic?

MACROD2 p.Trp43Arg (c.127T>C) is classified Uncertain significance in MACROD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.9843); Very rare (popmax 8.49e-05%, nfe).

How common is MACROD2 p.Trp43Arg (c.127T>C) in the general population?

MACROD2 p.Trp43Arg (c.127T>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about MACROD2 p.Trp43Arg (c.127T>C)?

AlphaMissense predicts likely pathogenic (score 0.9843) — an in-silico prediction, not a clinical call.

MACROD2 p.Trp43Arg

c.127T>C · VCV4548799

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9843 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9843	likely pathogenic
REVEL	0.313	indeterminate
SaProt	LLR -11.53	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 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 2,054 kb · p 0.068 · regional, not allelic
Overall
CADD	26.6	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

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,570 alleles

Overall 6.22e-05% 1/1,607,996 alleles · very rare exomes 1/1,455,694 · genomes 0/152,302 · joint denominator

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: MACROD2
Protein: p.Trp43Arg
Coding: c.127T>C
MANE Select: NM_001351661
Type: single nucleotide variant
Location: chr20:14002368 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.87 · 4 PDB
Residue 43: an α-helix

Full MACROD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FLRT3 p.Ser30= Likely benign ★★ same type
FLRT3 p.Thr419= Benign ★★ same type
MACROD2 p.Glu388Val Benign ★★ same type
FLRT3 p.Ala4Thr Uncertain significance ★ ⚠ same type
FLRT3 p.Arg203Cys Uncertain significance ★ same type
FLRT3 p.Arg330Cys Uncertain significance ★ ⚠ same type
FLRT3 p.Gly16Glu Uncertain significance ★ ⚠ same type
FLRT3 p.Ile604Asn 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/macrod2-p-trp43arg (accessed [today's date]).

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