Is MARK1 p.Asn331Ser (c.992A>G) pathogenic?

MARK1 p.Asn331Ser (c.992A>G) is classified Uncertain significance in MARK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely benign (0.0533); Ultra-rare (popmax 0.0117%, amr).

How common is MARK1 p.Asn331Ser (c.992A>G) in the general population?

MARK1 p.Asn331Ser (c.992A>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about MARK1 p.Asn331Ser (c.992A>G)?

AlphaMissense predicts likely benign (score 0.0533) — an in-silico prediction, not a clinical call.

MARK1 p.Asn331Ser

c.992A>G · rs376482473 · VCV2410132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0533 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0533	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -5.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP 0.64, phastCons 0.9
Regional constraint	o/e 0.85	unconstrained · MANE · 43 kb · p 0.00032 · regional, not allelic
Overall
CADD	14.66	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 0.0117% Admixed American · 7/59,902 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00192% 31/1,611,562 alleles · ultra-rare exomes 23/1,459,342 · genomes 8/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,557
African / African-American	0.0107%	9,358
European (non-Finnish)	0.00127%	78,537
South Asian	0.0011%	90,996

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: MARK1
Protein: p.Asn331Ser
Coding: c.992A>G
MANE Select: NM_018650
dbSNP: rs376482473
Type: single nucleotide variant
Location: chr1:220631117 (GRCh38)
Gene constraint: LOEUF 0.577 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 68.33 · 3 PDB
Residue 331: the uba domain

Full MARK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MARK1 p.Arg577Gln Uncertain significance ★★ ⚠ same type
MARK1 p.Ala541Pro Benign ★★ same type
MARK1 p.Ala352Thr Uncertain significance ★ ⚠ same type
MARK1 p.Ala442Asp Uncertain significance ★ ⚠ same type
MARK1 p.Arg268Gln Uncertain significance ★ ⚠ same type
MARK1 p.Arg391Gln Uncertain significance ★ ⚠ same type
MARK1 p.Arg421Cys Uncertain significance ★ ⚠ same type
MARK1 p.Arg42Trp 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/mark1-p-asn331ser (accessed [today's date]).

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