Is CA4 p.Met1Ile (c.3G>A) pathogenic?

CA4 p.Met1Ile (c.3G>A) is classified Uncertain significance in CA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-20). Very rare (popmax 0.00401%, afr).

How common is CA4 p.Met1Ile (c.3G>A) in the general population?

CA4 p.Met1Ile (c.3G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

CA4 p.Met1Ile

c.3G>A · rs1414235964 · VCV1513812

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 0.00401%, 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	0.496	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Overall
CADD	21.3	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 0.00401% African / African-American · 3/74,862 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00025% 4/1,602,476 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,954
South Asian	0.0011%	90,948

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: CA4
Protein: p.Met1Ile
Coding: c.3G>A
MANE Select: NM_000717
dbSNP: rs1414235964
Type: single nucleotide variant
Location: chr17:60150037 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.86 · 10 PDB

Full CA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CA4 c.745-9C>G Uncertain significance ★★ same type
CA4 p.Ala156Val Uncertain significance ★★ ⚠ same type
CA4 p.Ala308Ser Uncertain significance ★★ ⚠ same type
CA4 p.Arg279Pro Uncertain significance ★★ ⚠ same type
CA4 p.Arg50His Uncertain significance ★★ ⚠ same type
CA4 p.Arg50Ser Uncertain significance ★★ ⚠ same type
CA4 p.Asp131Asn Uncertain significance ★★ ⚠ same type
CA4 p.Asp206Glu 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/ca4-p-met1ile (accessed [today's date]).

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