Is MACROD2 p.Gln437= (c.1311A>G) pathogenic?

MACROD2 p.Gln437= (c.1311A>G) is classified Likely benign in MACROD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). Very rare (popmax 0.00968%, nfe).

How common is MACROD2 p.Gln437= (c.1311A>G) in the general population?

MACROD2 p.Gln437= (c.1311A>G) is very rare (popmax 0.00968%, nfe) (gnomAD).

MACROD2 p.Gln437=

c.1311A>G · rs374569449 · VCV2652209

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00968%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 1.7	GERP -0.77, phastCons 0.99
Overall
CADD	2.804	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00968% European (non-Finnish) · 114/1,177,618 alleles

Filtering AF 0.00819% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00762%

Overall 0.0077% 124/1,610,246 alleles · very rare exomes 117/1,458,284 · genomes 7/151,962 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00968%	10,330
Remaining individualsnot grpmax-eligible	0.00964%	10,379
Admixed American	0.00669%	14,956

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.Gln437=
Coding: c.1311A>G
MANE Select: NM_001351661
dbSNP: rs374569449
Type: single nucleotide variant
Location: chr20:16049840 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.87 · 4 PDB

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-gln437 (accessed [today's date]).

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