Is MACROD2 p.Ile35Phe (c.103A>T) pathogenic?

MACROD2 p.Ile35Phe (c.103A>T) is classified Uncertain significance in MACROD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-22). AlphaMissense: likely benign (0.1627); Absent from gnomAD v4.1.

How common is MACROD2 p.Ile35Phe (c.103A>T) in the general population?

MACROD2 p.Ile35Phe (c.103A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MACROD2 p.Ile35Phe (c.103A>T)?

AlphaMissense predicts likely benign (score 0.1627) — an in-silico prediction, not a clinical call.

MACROD2 p.Ile35Phe

c.103A>T · rs2052743339 · VCV2312899

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1627 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1627	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -10.14	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 2,054 kb · p 0.068 · regional, not allelic
Overall
CADD	22.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MACROD2
Protein: p.Ile35Phe
Coding: c.103A>T
MANE Select: NM_001351661
dbSNP: rs2052743339
Type: single nucleotide variant
Location: chr20:14002344 (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-ile35phe (accessed [today's date]).

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