Is ANOS1 p.Pro504Leu (c.1511C>T) pathogenic?

ANOS1 p.Pro504Leu (c.1511C>T) is classified Benign in ANOS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-03). AlphaMissense: likely benign (0.1261); Rare (popmax 0.148%, eas); Associated with hypogonadotropic hypogonadism 1 with or without anosmia.

What condition is associated with ANOS1 p.Pro504Leu (c.1511C>T)?

ANOS1 p.Pro504Leu (c.1511C>T) is associated with hypogonadotropic hypogonadism 1 with or without anosmia (ClinVar).

How common is ANOS1 p.Pro504Leu (c.1511C>T) in the general population?

ANOS1 p.Pro504Leu (c.1511C>T) is rare (popmax 0.148%, eas) (gnomAD).

What do computational predictors say about ANOS1 p.Pro504Leu (c.1511C>T)?

AlphaMissense predicts likely benign (score 0.1261) — an in-silico prediction, not a clinical call.

ANOS1 p.Pro504Leu

c.1511C>T · rs765611622 · VCV3013629

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1261 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 1 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.1261	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -7.20	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 6.6	GERP 4.6, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 199 kb · p 2.7e-06 · regional, not allelic
Overall
CADD	21.2	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 0.148% East Asian · 50/33,699 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.104%

Overall 0.0101% 122/1,205,285 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.148%	674
South Asian	0.083%	1,204
Admixed American	0.0109%	9,138
Remaining individualsnot grpmax-eligible	0.00421%	23,735
European (non-Finnish)	0.00202%	49,515

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: ANOS1
Protein: p.Pro504Leu
Coding: c.1511C>T
MANE Select: NM_000216
dbSNP: rs765611622
Type: single nucleotide variant
Location: chrX:8536881 (GRCh38)
Structure: AlphaFold pLDDT 76.88 · 1 PDB
Residue 504: the fibronectin type-iii 3 domain

Full ANOS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism 1 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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ANOS1 p.Arg262Ter Pathogenic ★★ same condition
ANOS1 p.Arg272Ter Pathogenic ★★ same condition
ANOS1 p.Arg423Ter Pathogenic ★★ same condition
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ANOS1 p.Arg457Ter Pathogenic/Likely pathogenic ★★ same condition

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/anos1-p-pro504leu (accessed [today's date]).

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