What do computational predictors say about KRT18 p.Ala92Pro (c.274G>C)?

AlphaMissense predicts likely pathogenic (score 0.9917) — an in-silico prediction, not a clinical call.

KRT18 p.Ala92Pro

Q: Is KRT18 p.Ala92Pro (c.274G>C) pathogenic?

KRT18 p.Ala92Pro (c.274G>C) is classified Benign in KRT18 (ClinVar, Single submitter, 3 submitters). AlphaMissense: likely pathogenic (0.9917); Common (popmax 19.8%, afr) — too common for a highly-penetrant pathogenic allele.

Q: How common is KRT18 p.Ala92Pro (c.274G>C) in the general population?

KRT18 p.Ala92Pro (c.274G>C) is common (popmax 19.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.274G>C · rs1434610693 · VCV1205843

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9917 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 19.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9917	likely pathogenic · top 2% in KRT18
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -14.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,665 bp · p 9.7e-13 · regional, not allelic
Overall
CADD	34.0	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 19.8% African / African-American · 10,633/53,838 alleles

Filtering AF 19.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 19.3%

Overall 2.87% 40,547/1,414,054 alleles · common exomes 508/1,328,096 · genomes 40,039/85,958 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	48.3%	2
African / African-Americangrpmax	19.8%	5
Admixed American	8.15%	12
Finnishnot grpmax-eligible	7%	14
Ashkenazi Jewishnot grpmax-eligible	4.02%	25
Middle Eastern	3.93%	25
East Asian	3.82%	26
European (non-Finnish)	1.71%	58
South Asian	1.39%	72
Remaining individualsnot grpmax-eligible	1.05%	95

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: KRT18
Protein: p.Ala92Pro
Coding: c.274G>C
MANE Select: NM_000224
dbSNP: rs1434610693
Type: single nucleotide variant
Location: chr12:52949447 (GRCh38)
Gene constraint: LOEUF 0.411 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.18
Residue 92: the if rod domain; the 'necessary for interaction with pnn' region; the 'interaction with tradd' region; the 'coil 1a' region

Full KRT18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT18 p.Gly69Ala Uncertain significance ★★ ⚠ same type
KRT18 p.Ser230Thr Likely benign ★★ same type
KRT18 p.Ala173Gly Uncertain significance ★ ⚠ same type
KRT18 p.Ala395Val Uncertain significance ★ ⚠ same type
KRT18 p.Arg186His Uncertain significance ★ ⚠ same type
KRT18 p.Arg330His Uncertain significance ★ ⚠ same type
KRT18 p.Arg353Trp Uncertain significance ★ same type
KRT18 p.Arg381His 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/krt18-p-ala92pro (accessed [today's date]).

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