Is AMFR p.Arg185Gln (c.554G>A) pathogenic?

AMFR p.Arg185Gln (c.554G>A) is classified Uncertain significance in AMFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.1874); Ultra-rare (popmax 0.0358%, nfe).

How common is AMFR p.Arg185Gln (c.554G>A) in the general population?

AMFR p.Arg185Gln (c.554G>A) is ultra-rare (popmax 0.0358%, nfe) (gnomAD).

What do computational predictors say about AMFR p.Arg185Gln (c.554G>A)?

AlphaMissense predicts likely benign (score 0.1874) — an in-silico prediction, not a clinical call.

AMFR p.Arg185Gln

c.554G>A · rs144323704 · VCV2588201

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1874 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0358%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1874	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -11.13	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 20 kb · p 0.00011 · regional, not allelic
Overall
CADD	32.0	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 0.0358% European (non-Finnish) · 423/1,180,024 alleles

Filtering AF 0.033% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0319%

Overall 0.0286% 462/1,613,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0358%	2,790
Remaining individualsnot grpmax-eligible	0.0288%	3,471
Finnishnot grpmax-eligible	0.0266%	3,766
African / African-American	0.00534%	18,726

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: AMFR
Protein: p.Arg185Gln
Coding: c.554G>A
MANE Select: NM_001144
dbSNP: rs144323704
Type: single nucleotide variant
Location: chr16:56408076 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 13 PDB
Residue 185: a UniProt-annotated variant site (in spg89; pathogenic)

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

Similar variants

AMFR p.Arg307Cys Uncertain significance ★★ ⚠ same type
AMFR p.Arg389His Uncertain significance ★★ ⚠ same type
AMFR c.707+1G>A Likely pathogenic ★ same type
AMFR p.Cys364Ter Pathogenic ★ same type
AMFR p.Ala231Ser Uncertain significance ★ ⚠ same type
AMFR p.Ala324Val Uncertain significance ★ ⚠ same type
AMFR p.Ala385Thr Uncertain significance ★ ⚠ same type
AMFR p.Ala407Pro 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/amfr-p-arg185gln (accessed [today's date]).

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