Is SIX3 p.Met1Val (c.1A>G) pathogenic?

SIX3 p.Met1Val (c.1A>G) is classified Conflicting classifications of pathogenicity in SIX3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-05-11). Very rare (popmax 0.0011%, sas).

How common is SIX3 p.Met1Val (c.1A>G) in the general population?

SIX3 p.Met1Val (c.1A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

SIX3 p.Met1Val

c.1A>G · rs1553337590 · VCV504413

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.715	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,760 alleles

Overall 6.98e-05% 1/1,433,228 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: SIX3
Protein: p.Met1Val
Coding: c.1A>G
MANE Select: NM_005413
dbSNP: rs1553337590
Type: single nucleotide variant
Location: chr2:44942105 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38

Full SIX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIX3 p.Ala72Val Uncertain significance ★★ ⚠ same type
SIX3 p.Arg146Cys Uncertain significance ★★ ⚠ same type
SIX3 p.Arg201His Uncertain significance ★★ ⚠ same type
SIX3 p.Arg281Ser Uncertain significance ★★ same type
SIX3 p.Asp205His Uncertain significance ★★ ⚠ same type
SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same type
SIX3 p.Gly244Cys Uncertain significance ★★ ⚠ same type
SIX3 p.Gly317Ser 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/six3-p-met1val (accessed [today's date]).

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