Is MACROD2 p.Ile205Val (c.613A>G) pathogenic?

MACROD2 p.Ile205Val (c.613A>G) is classified Uncertain significance in MACROD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.0737); Ultra-rare (popmax 0.0187%, afr).

How common is MACROD2 p.Ile205Val (c.613A>G) in the general population?

MACROD2 p.Ile205Val (c.613A>G) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about MACROD2 p.Ile205Val (c.613A>G)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

MACROD2 p.Ile205Val

c.613A>G · VCV4102116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -5.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 2.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 2,054 kb · p 0.068 · regional, not allelic
Overall
CADD	16.11	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,916 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.000992% 16/1,613,712 alleles · ultra-rare exomes 11/1,461,522 · genomes 5/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,351
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)	8.48e-05%	1,179,778

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.Ile205Val
Coding: c.613A>G
MANE Select: NM_001351661
Type: single nucleotide variant
Location: chr20:15499815 (GRCh38)
Gene constraint: LOEUF 0.724 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.87 · 4 PDB
Residue 205: the macro domain; 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-ile205val (accessed [today's date]).

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