Is A1CF p.Val540Leu (c.1618G>C) pathogenic?

A1CF p.Val540Leu (c.1618G>C) is classified Uncertain significance in A1CF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: likely benign (0.1001); Absent from gnomAD v4.1.

How common is A1CF p.Val540Leu (c.1618G>C) in the general population?

A1CF p.Val540Leu (c.1618G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about A1CF p.Val540Leu (c.1618G>C)?

AlphaMissense predicts likely benign (score 0.1001) — an in-silico prediction, not a clinical call.

A1CF p.Val540Leu

c.1618G>C · rs1458838950 · VCV2279286

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1001 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,607,382)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1001	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.34	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 0.41	GERP -0.12, phastCons 0.035
Regional constraint	o/e 0.91	unconstrained · MANE · 53 kb · p 0.014 · regional, not allelic
Overall
CADD	12.84	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V548L vs ClinVar V540L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,607,382). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: A1CF
Protein: p.Val540Leu
Coding: c.1618G>C
MANE Select: NM_014576
dbSNP: rs1458838950
Type: single nucleotide variant
Location: chr10:50806872 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.70 · 1 PDB

Full A1CF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

A1CF p.Ala195= Benign ★★ same type
A1CF p.Cys76= Benign ★★ same type
A1CF p.Gly390Ser Likely benign ★★ same type
A1CF p.Ser294= Benign ★★ same type
A1CF c.100-6618G>A Uncertain significance ★ same type
A1CF c.100-6622G>A Uncertain significance ★ same type
A1CF p.Ala383Val Uncertain significance ★ ⚠ same type
A1CF p.Ala462Ser 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/a1cf-p-val540leu (accessed [today's date]).

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