Is MACROD1 p.Phe272Val (c.814T>G) pathogenic?

MACROD1 p.Phe272Val (c.814T>G) is classified Uncertain significance in MACROD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely pathogenic (0.9712); Very rare (popmax 0.00017%, nfe).

How common is MACROD1 p.Phe272Val (c.814T>G) in the general population?

MACROD1 p.Phe272Val (c.814T>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about MACROD1 p.Phe272Val (c.814T>G)?

AlphaMissense predicts likely pathogenic (score 0.9712) — an in-silico prediction, not a clinical call.

MACROD1 p.Phe272Val

c.814T>G · rs2539454749 · VCV2409746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9712	likely pathogenic · top 8% in MACROD1
REVEL	0.258	benign-leaning
SaProt	LLR -11.95	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 167 kb · p 0.54 · regional, not allelic
Overall
CADD	27.2	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

Grpmax group 0.00017% European (non-Finnish) · 2/1,177,656 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,455,478 alleles · very rare

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: MACROD1
Protein: p.Phe272Val
Coding: c.814T>G
MANE Select: NM_014067
dbSNP: rs2539454749
Type: single nucleotide variant
Location: chr11:63999533 (GRCh38)
Gene constraint: LOEUF 1.326 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.29 · 2 PDB
Residue 272: the macro domain; a binding site

Full MACROD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FLRT1 p.Arg364Gln Uncertain significance ★★ same type
FLRT1 p.Asn305Lys Uncertain significance ★★ same type
FLRT1 p.Ser146Leu Uncertain significance ★★ same type
FLRT1 p.Thr13Arg Uncertain significance ★★ same type
FLRT1 p.Ala96= Benign ★★ same type
FLRT1 p.Phe36= Benign ★★ same type
FLRT1 p.Arg130Gln Uncertain significance ★ same type
FLRT1 p.Arg294Leu 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/macrod1-p-phe272val (accessed [today's date]).

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