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

SIAE p.Met1Val (c.1A>G) is classified Uncertain significance in SIAE (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-28). Very rare (popmax 0.00267%, afr).

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

SIAE p.Met1Val (c.1A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

SIAE p.Met1Val

c.1A>G · rs764040566 · VCV1370670

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.627	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.92, phastCons 1
Overall
CADD	18.44	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 0.00267% African / African-American · 2/74,964 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,613,422 alleles · very rare exomes 10/1,461,314 · genomes 2/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,482
Remaining individualsnot grpmax-eligible	0.0016%	62,398
European (non-Finnish)	0.000763%	131,083

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: SIAE
Protein: p.Met1Val
Coding: c.1A>G
MANE Select: NM_170601
dbSNP: rs764040566
Type: single nucleotide variant
Location: chr11:124673708 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.26

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

Similar variants

SIAE p.Met1Ile Uncertain significance ★ same residue
SIAE p.Met1Thr Uncertain significance ★ same residue
SIAE p.Ala385Thr Uncertain significance ★★ ⚠ same type
SIAE p.Arg301His Uncertain significance ★★ ⚠ same type
SIAE p.Arg306Cys Uncertain significance ★★ ⚠ same type
SIAE p.Cys196Phe Uncertain significance ★★ ⚠ same type
SIAE p.Cys449Ser Uncertain significance ★★ ⚠ same type
SIAE p.Gln309Arg 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/siae-p-met1val (accessed [today's date]).

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