Is AFG1L p.His73Arg (c.218A>G) pathogenic?

AFG1L p.His73Arg (c.218A>G) is classified Uncertain significance in AFG1L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.0542); Ultra-rare (popmax 0.0364%, nfe).

How common is AFG1L p.His73Arg (c.218A>G) in the general population?

AFG1L p.His73Arg (c.218A>G) is ultra-rare (popmax 0.0364%, nfe) (gnomAD).

What do computational predictors say about AFG1L p.His73Arg (c.218A>G)?

AlphaMissense predicts likely benign (score 0.0542) — an in-silico prediction, not a clinical call.

AFG1L p.His73Arg

c.218A>G · rs143222151 · VCV3092822

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0542 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0364%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0542	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -3.21	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 0.57	GERP -1.4, phastCons 0.002
Regional constraint	o/e 0.94	unconstrained · MANE · 227 kb · p 0.14 · regional, not allelic
Overall
CADD	12.31	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0364% European (non-Finnish) · 429/1,180,044 alleles

Filtering AF 0.0335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0323%

Overall 0.0279% 451/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0364%	2,751
Admixed American	0.015%	6,667
Remaining individualsnot grpmax-eligible	0.0096%	10,415
African / African-American	0.00801%	12,490
East Asian	0.00223%	44,894

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: AFG1L
Protein: p.His73Arg
Coding: c.218A>G
MANE Select: NM_145315
dbSNP: rs143222151
Type: single nucleotide variant
Location: chr6:108323903 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.92

Full AFG1L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFG1L p.Ala2Val Uncertain significance ★ ⚠ same type
AFG1L p.Ala305Thr Uncertain significance ★ ⚠ same type
AFG1L p.Ala339Gly Uncertain significance ★ ⚠ same type
AFG1L p.Ala60Pro Uncertain significance ★ ⚠ same type
AFG1L p.Arg12Ser Uncertain significance ★ ⚠ same type
AFG1L p.Arg160Trp Uncertain significance ★ ⚠ same type
AFG1L p.Arg176Cys Uncertain significance ★ ⚠ same type
AFG1L p.Arg176His 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/afg1l-p-his73arg (accessed [today's date]).

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