Is MACROD2 p.Ala440Val (c.1319C>T) pathogenic?

MACROD2 p.Ala440Val (c.1319C>T) is classified Uncertain significance in MACROD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-04). AlphaMissense: likely benign (0.0796); Ultra-rare (popmax 0.0203%, amr).

How common is MACROD2 p.Ala440Val (c.1319C>T) in the general population?

MACROD2 p.Ala440Val (c.1319C>T) is ultra-rare (popmax 0.0203%, amr) (gnomAD).

What do computational predictors say about MACROD2 p.Ala440Val (c.1319C>T)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

MACROD2 p.Ala440Val

c.1319C>T · VCV4102113

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.1	GERP -3.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 2,054 kb · p 0.068 · regional, not allelic
Overall
CADD	16.26	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A417V vs ClinVar A440V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0203% Admixed American · 12/59,040 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00912%

Overall 0.00349% 56/1,604,456 alleles · ultra-rare exomes 46/1,454,748 · genomes 10/149,708 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0203%	4,920
European (non-Finnish)	0.00349%	28,663
Remaining individualsnot grpmax-eligible	0.00161%	62,002
Finnishnot grpmax-eligible	0.00159%	62,742
South Asian	0.0011%	90,878

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.Ala440Val
Coding: c.1319C>T
MANE Select: NM_001351661
Type: single nucleotide variant
Location: chr20:16049848 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.87 · 4 PDB
Residue 417 UniProt numbering: the 'disordered' region

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

Similar variants

MACROD2 p.Ala440Thr Uncertain significance ★ ⚠ same residue
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

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-ala440val (accessed [today's date]).

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