Is AFDN p.Thr1218= (c.3654G>A) pathogenic?

AFDN p.Thr1218= (c.3654G>A) is classified Benign in AFDN (ClinVar, Single submitter, 1 submitter; last evaluated 2017-10-24). Common (popmax 5.25%, amr) — too common for a highly-penetrant pathogenic allele.

AFDN p.Thr1218=

Q: How common is AFDN p.Thr1218= (c.3654G>A) in the general population?

AFDN p.Thr1218= (c.3654G>A) is common (popmax 5.25%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3654G>A · rs144312007 · VCV771409

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 5.25%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.2	GERP -3.1
Overall
CADD	0.875	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.25% Admixed American · 3,085/58,758 alleles

Filtering AF 5.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.03%

Overall 0.2% 3,213/1,606,634 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	5.25%	19
Remaining individualsnot grpmax-eligible	0.105%	956
African / African-American	0.0469%	2,132
South Asian	0.00335%	29,887
European (non-Finnish)	0.00213%	47,056

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: AFDN
Protein: p.Thr1218=
Coding: c.3654G>A
MANE Select: NM_001386888
dbSNP: rs144312007
Type: single nucleotide variant
Location: chr6:167948301 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.69 · 6 PDB
Residue 1218: the 'disordered' region

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

Similar variants

AFDN p.Ile438Val Uncertain significance ★★ ⚠ same type
AFDN c.4968+1G>C Uncertain significance ★ same type
AFDN p.Arg1634Leu Uncertain significance ★ ⚠ same type
AFDN p.Arg1717Ter Uncertain significance ★ same type
AFDN p.Arg999His Uncertain significance ★ ⚠ same type
AFDN p.Asp1176Glu Uncertain significance ★ ⚠ same type
AFDN p.Asp1516Ala Uncertain significance ★ ⚠ same type
AFDN p.Asp539His 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/afdn-p-thr1218 (accessed [today's date]).

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