Is MACROD1 p.Ser8Ala (c.22T>G) pathogenic?

MACROD1 p.Ser8Ala (c.22T>G) is classified Uncertain significance in MACROD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely benign (0.0635); Very rare (popmax 0.00773%, afr).

How common is MACROD1 p.Ser8Ala (c.22T>G) in the general population?

MACROD1 p.Ser8Ala (c.22T>G) is very rare (popmax 0.00773%, afr) (gnomAD).

What do computational predictors say about MACROD1 p.Ser8Ala (c.22T>G)?

AlphaMissense predicts likely benign (score 0.0635) — an in-silico prediction, not a clinical call.

MACROD1 p.Ser8Ala

c.22T>G · rs899008449 · VCV2340088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00773%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0635	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -5.00	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 0.24	GERP 1.2, phastCons 0.67
Regional constraint	o/e 1.03	unconstrained · MANE · 167 kb · p 0.54 · regional, not allelic
Overall
CADD	17.12	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 0.00773% African / African-American · 5/64,682 alleles

Filtering AF 0.00296% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00194%

Overall 0.000541% 7/1,294,648 alleles · very rare exomes 1/1,142,576 · genomes 6/152,072 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00773%	12,936
Admixed American	0.00418%	23,898
Remaining individualsnot grpmax-eligible	0.00205%	48,734

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.Ser8Ala
Coding: c.22T>G
MANE Select: NM_014067
dbSNP: rs899008449
Type: single nucleotide variant
Location: chr11:64165973 (GRCh38)
Gene constraint: LOEUF 1.326 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.29 · 2 PDB

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-ser8ala (accessed [today's date]).

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