Is A1CF p.Ser378Phe (c.1133C>T) pathogenic?

A1CF p.Ser378Phe (c.1133C>T) is classified Uncertain significance in A1CF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: ambiguous (0.5356); Absent from gnomAD v4.1.

How common is A1CF p.Ser378Phe (c.1133C>T) in the general population?

A1CF p.Ser378Phe (c.1133C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about A1CF p.Ser378Phe (c.1133C>T)?

AlphaMissense predicts ambiguous (score 0.5356) — an in-silico prediction, not a clinical call.

A1CF p.Ser378Phe

c.1133C>T · VCV4049130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5356 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.5356	ambiguous
REVEL	0.457	indeterminate
SaProt	LLR -8.45	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 53 kb · p 0.014 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: A1CF
Protein: p.Ser378Phe
Coding: c.1133C>T
MANE Select: NM_014576
Type: single nucleotide variant
Location: chr10:50816014 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.70 · 1 PDB
Residue 378: the 'required for nuclear localization' region

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-ser378phe (accessed [today's date]).

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