Is ANKH p.Pro308Ala (c.922C>G) pathogenic?

ANKH p.Pro308Ala (c.922C>G) is classified Uncertain significance in ANKH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-01-28). AlphaMissense: likely benign (0.2058); Very rare (popmax 0.000932%, nfe); Associated with intellectual disability.

What condition is associated with ANKH p.Pro308Ala (c.922C>G)?

ANKH p.Pro308Ala (c.922C>G) is associated with intellectual disability (ClinVar).

How common is ANKH p.Pro308Ala (c.922C>G) in the general population?

ANKH p.Pro308Ala (c.922C>G) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about ANKH p.Pro308Ala (c.922C>G)?

AlphaMissense predicts likely benign (score 0.2058) — an in-silico prediction, not a clinical call.

ANKH p.Pro308Ala

c.922C>G · rs1057521543 · VCV383180

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2058 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability

Computational evidence

Protein change
AlphaMissense	0.2058	likely benign
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -6.46	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 160 kb · p 1.1e-21 · regional, not allelic
Overall
CADD	26.7	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 0.000932% European (non-Finnish) · 11/1,179,908 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000821% 12/1,461,732 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.000932%	107,264

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.Pro308Ala
Coding: c.922C>G
MANE Select: NM_054027
dbSNP: rs1057521543
Type: single nucleotide variant
Location: chr5:14741916 (GRCh38)
Gene constraint: LOEUF 0.463 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 84.57

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

Disease context

intellectual disability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
ANKH p.Asn306Asp 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-pro308ala (accessed [today's date]).

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