Is KERA p.Pro208Arg (c.623C>G) pathogenic?

KERA p.Pro208Arg (c.623C>G) is classified Uncertain significance in KERA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-22). AlphaMissense: likely pathogenic (0.9884); Very rare (popmax 0.00167%, amr); Associated with cornea plana 2.

What condition is associated with KERA p.Pro208Arg (c.623C>G)?

KERA p.Pro208Arg (c.623C>G) is associated with cornea plana 2 (ClinVar).

How common is KERA p.Pro208Arg (c.623C>G) in the general population?

KERA p.Pro208Arg (c.623C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about KERA p.Pro208Arg (c.623C>G)?

AlphaMissense predicts likely pathogenic (score 0.9884) — an in-silico prediction, not a clinical call.

KERA p.Pro208Arg

c.623C>G · rs778354357 · VCV1687461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cornea plana 2

Computational evidence

Protein change
AlphaMissense	0.9884	likely pathogenic · top 6% in KERA
REVEL	0.607	indeterminate
SaProt	LLR -9.84	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 4,932 bp · p 0.22 · regional, not allelic
Overall
CADD	28.1	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 0.00167% Admixed American · 1/59,726 alleles

Overall 6.21e-05% 1/1,611,110 alleles · very rare exomes 0/1,460,016 · genomes 1/151,094 · joint denominator

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: KERA
Protein: p.Pro208Arg
Coding: c.623C>G
MANE Select: NM_007035
dbSNP: rs778354357
Type: single nucleotide variant
Location: chr12:91055659 (GRCh38)
Gene constraint: LOEUF 1.284 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.42

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

Disease context

cornea plana 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KERA p.Arg279Ter Pathogenic ★★ same condition
KERA p.Asn247Ser Pathogenic ★★ same condition
KERA p.Val23= Benign ★★ same condition
KERA p.Arg313Ter Pathogenic ★ same condition
KERA p.Asn176Lys Likely pathogenic ★ same condition
KERA p.Asn81Ser Likely pathogenic ★ same condition
KERA p.Gly111Arg Uncertain significance ★ ⚠ same condition
KERA p.Tyr77His Uncertain significance ★ ⚠ 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/kera-p-pro208arg (accessed [today's date]).

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