Is ADM p.Pro177Ala (c.529C>G) pathogenic?

ADM p.Pro177Ala (c.529C>G) is classified Uncertain significance in ADM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely benign (0.0548); Ultra-rare (popmax 0.0385%, amr).

How common is ADM p.Pro177Ala (c.529C>G) in the general population?

ADM p.Pro177Ala (c.529C>G) is ultra-rare (popmax 0.0385%, amr) (gnomAD).

What do computational predictors say about ADM p.Pro177Ala (c.529C>G)?

AlphaMissense predicts likely benign (score 0.0548) — an in-silico prediction, not a clinical call.

ADM p.Pro177Ala

c.529C>G · rs373720232 · VCV2347307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0548 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0385%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0548	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -5.93	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 -0.52
Regional constraint	o/e 1.00	unconstrained · MANE · 937 bp · p 0.95 · regional, not allelic
Overall
CADD	2.388	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0385% Admixed American · 19/49,376 alleles

Filtering AF 0.0251% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00672% 105/1,562,692 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.1%	91
Admixed Americangrpmax	0.0385%	2,599
African / African-American	0.00688%	14,532
European (non-Finnish)	0.00562%	17,797
Remaining individualsnot grpmax-eligible	0.005%	20,009
East Asian	0.00452%	22,109
South Asian	0.00118%	84,676

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ADM
Protein: p.Pro177Ala
Coding: c.529C>G
MANE Select: NM_001124
dbSNP: rs373720232
Type: single nucleotide variant
Location: chr11:10306612 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 62.35 · 8 PDB
Residue 177: the 'disordered' region

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

Similar variants

ADM p.Ser50Arg Benign ★★ same type
ADM p.Ala22Ser Uncertain significance ★ ⚠ same type
ADM p.Ala38Ser Uncertain significance ★ ⚠ same type
ADM p.Ala38Val Uncertain significance ★ ⚠ same type
ADM p.Ala87Val Uncertain significance ★ ⚠ same type
ADM p.Arg23Trp Uncertain significance ★ ⚠ same type
ADM p.Arg89His Uncertain significance ★ ⚠ same type
ADM p.Arg94Leu 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/adm-p-pro177ala (accessed [today's date]).

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