Is A1CF p.Ile73Thr (c.218T>C) pathogenic?

A1CF p.Ile73Thr (c.218T>C) is classified Uncertain significance in A1CF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: likely pathogenic (0.9646); Very rare (popmax 0.000848%, nfe).

How common is A1CF p.Ile73Thr (c.218T>C) in the general population?

A1CF p.Ile73Thr (c.218T>C) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about A1CF p.Ile73Thr (c.218T>C)?

AlphaMissense predicts likely pathogenic (score 0.9646) — an in-silico prediction, not a clinical call.

A1CF p.Ile73Thr

c.218T>C · rs139143762 · VCV3135943

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9646	likely pathogenic
REVEL	0.243	benign-leaning
SaProt	LLR -12.11	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 53 kb · p 0.014 · regional, not allelic
Overall
CADD	25.7	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

Grpmax group 0.000848% European (non-Finnish) · 10/1,179,840 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000684% 10/1,461,598 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: A1CF
Protein: p.Ile73Thr
Coding: c.218T>C
MANE Select: NM_014576
dbSNP: rs139143762
Type: single nucleotide variant
Location: chr10:50844004 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.70 · 1 PDB
Residue 73: the rrm 1 domain

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

Similar variants

A1CF p.Ile73Met Uncertain significance ★ ⚠ same residue
A1CF p.Ile73Val Uncertain significance ★ ⚠ same residue
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

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-ile73thr (accessed [today's date]).

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