Is ANKH p.Pro477= (c.1431G>A) pathogenic?

ANKH p.Pro477= (c.1431G>A) is classified Likely benign in ANKH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0547%, nfe).

How common is ANKH p.Pro477= (c.1431G>A) in the general population?

ANKH p.Pro477= (c.1431G>A) is ultra-rare (popmax 0.0547%, nfe) (gnomAD).

ANKH p.Pro477=

c.1431G>A · rs151281757 · VCV1197982

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0547%, nfe)

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 -20	GERP -2.9
Overall
CADD	0.01	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0547% European (non-Finnish) · 646/1,180,010 alleles

Filtering AF 0.0512% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0498%

Overall 0.0471% 760/1,614,128 alleles · ultra-rare exomes 727/1,461,860 · genomes 33/152,268 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0592%	1,689
European (non-Finnish)grpmax	0.0547%	1,827
South Asian	0.0527%	1,898
Admixed American	0.02%	5,002
Middle Eastern	0.0165%	6,062
African / African-American	0.012%	8,337
Finnishnot grpmax-eligible	0.00937%	10,671
East Asian	0.00223%	44,862

Remaining individuals 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: ANKH
Protein: p.Pro477=
Coding: c.1431G>A
MANE Select: NM_054027
dbSNP: rs151281757
Type: single nucleotide variant
Location: chr5:14711245 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.57
Residue 477: the 'disordered' region

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

Similar variants

ANKH p.Pro477Leu Uncertain significance ★★ ⚠ same residue
ANKH c.1142-4A>G Pathogenic/Likely pathogenic ★★ same type
ANKH c.96+5G>A Uncertain significance ★★ same type
ANKH c.*3752G>A Uncertain significance ★★ same type
ANKH p.Ala136Thr Uncertain significance ★★ ⚠ same type
ANKH p.Ala201Thr Uncertain significance ★★ ⚠ same type
ANKH p.Ala448Thr Uncertain significance ★★ same type
ANKH p.Arg453Gln 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/ankh-p-pro477 (accessed [today's date]).

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