Is AFMID p.Gly166Arg (c.496G>A) pathogenic?

AFMID p.Gly166Arg (c.496G>A) is classified Uncertain significance in AFMID (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-26). AlphaMissense: likely pathogenic (0.8044); Ultra-rare (popmax 0.0254%, afr).

How common is AFMID p.Gly166Arg (c.496G>A) in the general population?

AFMID p.Gly166Arg (c.496G>A) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about AFMID p.Gly166Arg (c.496G>A)?

AlphaMissense predicts likely pathogenic (score 0.8044) — an in-silico prediction, not a clinical call.

AFMID p.Gly166Arg

c.496G>A · VCV3504722

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8044 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8044	likely pathogenic · top 5% in AFMID
REVEL	0.914	moderately pathogenic-leaning
SaProt	LLR -15.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 20 kb · p 0.53 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0254% African / African-American · 19/74,916 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00223% 36/1,612,346 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,943
East Asian	0.00446%	22,419
Admixed American	0.00335%	29,890
Remaining individualsnot grpmax-eligible	0.0032%	31,206
South Asian	0.0011%	90,672
European (non-Finnish)	0.000848%	117,937

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: AFMID
Protein: p.Gly166Arg
Coding: c.496G>A
MANE Select: NM_001010982
Type: single nucleotide variant
Location: chr17:78205121 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.39

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

Similar variants

AFMID p.Ala41Asp Uncertain significance ★ ⚠ same type
AFMID p.Arg238His Uncertain significance ★ ⚠ same type
AFMID p.Arg35Gln Uncertain significance ★ ⚠ same type
AFMID p.Asn291Lys Uncertain significance ★ ⚠ same type
AFMID p.Asp247Asn Uncertain significance ★ ⚠ same type
AFMID p.Asp247Glu Uncertain significance ★ ⚠ same type
AFMID p.Asp247Val Uncertain significance ★ ⚠ same type
AFMID p.Cys237Gly 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/afmid-p-gly166arg (accessed [today's date]).

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