Is AHR p.Arg554Lys (c.1661G>A) pathogenic?

AHR p.Arg554Lys (c.1661G>A) is classified Benign in AHR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0565); Common (popmax 45.6%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about AHR p.Arg554Lys (c.1661G>A)?

AlphaMissense predicts likely benign (score 0.0565) — an in-silico prediction, not a clinical call.

AHR p.Arg554Lys

Q: How common is AHR p.Arg554Lys (c.1661G>A) in the general population?

AHR p.Arg554Lys (c.1661G>A) is common (popmax 45.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1661G>A · rs2066853 · VCV1168239

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0565 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 45.6%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0565	likely benign
REVEL	0.04	moderately benign-leaning
SaProt	LLR -4.82	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 1.6	GERP 0.67, phastCons 0.29
Regional constraint	o/e 1.12	unconstrained · MANE · 4,073 bp · p 0.0061 · regional, not allelic
Overall
CADD	4.754	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 45.6% African / African-American · 34,155/74,918 alleles

Filtering AF 45.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 45%

Overall 13.4% 216,831/1,613,866 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	45.6%	2
East Asian	39.9%	3
Middle Eastern	15.3%	7
Remaining individualsnot grpmax-eligible	15.2%	7
Admixed American	13.9%	7
South Asian	13.8%	7
Ashkenazi Jewishnot grpmax-eligible	12.4%	8
Finnishnot grpmax-eligible	11.2%	9
European (non-Finnish)	10.4%	10
Amishnot grpmax-eligible	9.54%	10

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: AHR
Protein: p.Arg554Lys
Coding: c.1661G>A
MANE Select: NM_001621
dbSNP: rs2066853
Type: single nucleotide variant
Location: chr7:17339486 (GRCh38)
Gene constraint: LOEUF 0.606 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 56.88 · 3 PDB
Residue 554: a UniProt-annotated variant site (in)

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

Similar variants

AHR p.Arg554= Likely benign ★ same residue
AHR p.Ala313Thr Uncertain significance ★★ ⚠ same type
AHR p.Ala459Ser Uncertain significance ★★ ⚠ same type
AHR p.Arg352Trp Uncertain significance ★★ ⚠ same type
AHR p.Asn179His Uncertain significance ★★ ⚠ same type
AHR p.Asn238Ser Uncertain significance ★★ ⚠ same type
AHR p.Asn789Ser Uncertain significance ★★ ⚠ same type
AHR p.Asp841Asn 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/ahr-p-arg554lys (accessed [today's date]).

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